Transdermal carrier

ABSTRACT

Improved formulations for topical treatment that ensure at least localized transdermal or systemic delivery of an active agent through skin, nails or hair follicles are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/757,703 filed 23 Dec. 2015, which application is acontinuation-in-part of PCT application PCT/US2014/072239, having aninternational filing date of 23 Dec. 2014; and claims priority from U.S.Provisional Application No. 62/176,416, filed 17 Feb. 2015; U.S.Provisional Application No. 62/198,605, filed 29 Jul. 2015; U.S.Provisional Application No. 62/187,756, filed 1 Jul. 2015; U.S.Provisional Application No. 62/176,418, filed 17 Feb. 2015; U.S.Provisional Application No. 62/191,952, filed 13 Jul. 2015; U.S.Provisional Application No. 62/178,232, filed 6 Apr. 2015; U.S.Provisional Application No. 62/198,599, filed 29 Jul. 2015; U.S.Provisional Application No. 62/177,814, filed 24 Mar. 2015; U.S.Provisional Application No. 62/261,167, filed 30 Nov. 2015; U.S.Provisional Application No. 62/176,438, filed 17 Feb. 2015; U.S.Provisional Application No. 62/176,417, filed 17 Feb. 2015; U.S.Provisional Application No. 62/176,414, filed 17 Feb. 2015; U.S.Provisional Application No. 62/176,415, filed 17 Feb. 2015; U.S.Provisional Application No. 62/176,419, filed 17 Feb. 2015; U.S.Provisional Application No. 62/178,192, filed 2 Apr. 2015; U.S.Provisional Application No. 62/238,012, filed 6 Oct. 2015; and U.S.Provisional Application No. 62/178,193, filed 2 Apr. 2015. The contentsof these documents are hereby incorporated by reference in theirentirety.

TECHNICAL FIELD

The invention is in the field of topical treatments that effecttransdermal transport of an active agent through the skin, nail or hairfollicles. More particularly it concerns direct application of apenetrating formulation containing an active agent topically to asubject.

BACKGROUND ART

Various formulations have been proposed to effect transport oftherapeutically active agents topically through the skin and hairfollicles. For example, US2009/0053290 describes formulations fortransdermal delivery of active ingredients which formulations comprise acombination of two penetrants, the first being present in amounts fromabout 1% to about 20% by weight (% w/w) and typified as benzyl alcoholand a second penetrant typified by a lecithin organogel present in anamount of 0.5%-20% w/w. In preferred compositions, the benzyl alcohol ispresent in a significantly higher amount than the lecithin organogel. Insome embodiments, the second penetrant is a combination of the lecithinorganogel with Pluronic®. It is suggested that the percentage of thecombination of Pluronic® and lecithin organogel in the formulation be0.5-15% w/w.

PCT publication WO2014/209910 discloses topical formulations whereinbenzyl alcohol is present in about 2% w/w of the composition andlecithin organogel while permitted to be present in the range of 0.5%45%w/w is preferably present in a concentration lower than that of thebenzyl alcohol. A suggested preferred composition is 2% benzyl alcoholand 0.6% lecithin organogel. This publication specifically excludes theuse of poloxamers such as Pluronic®.

Other compositions that employ lecithin organogels for transdermaladministration are described in Raut, S., et al., Acta Pharm Sin (2012)2:8-15 and reviewed by Elnaggar, Y., S-R., et al., J. Controlled Rel.(2014) 180:10-24.

It has now been found, unexpectedly, that high concentrations oflecithin organogel in comparison to the concentration of benzyl alcohol(or its similars) lead to effective delivery of drugs topically toeffect local or overall systemic administration and, further, that theinclusion of a nonionic detergent and polar solvent and/or a bile saltis helpful. In some embodiments, anhydrous formulations can be employed.

DISCLOSURE OF THE INVENTION

It has surprisingly been found that using the formulations and methodsof the present invention, particularly effective transdermal local orsystemic delivery of therapeutically active agents can be achieved.Without intending to be bound by any theory, applicants believe that theimprovement is due to the enhanced ability of the formulations of theinvention to permit penetration of the skin, nails or hair follicles bythe active ingredient or ingredients in the formulations. Improvementshave also been made in conducting the method of applying theseformulations.

Thus, in one aspect, the invention is directed to a formulation fortransdermal delivery of a therapeutic agent through the skin or hairfollicle. The formulation comprises an active agent in an amounteffective for treatment along with benzyl alcohol at 0.5-20% w/w andlecithin organogel at 25-70% w/w. Additional components, such asantioxidants, may also be included.

In some embodiments, the formulation also contains surfactant,typically, nonionic surfactant at 2-25% w/w along with a polar solventwherein the polar solvent is present in an amount at least in molarexcess of the nonionic surfactant. In these embodiments, typically, thecomposition comprises the above-referenced amounts of lecithin organogeland benzyl alcohol along with active ingredient with sufficient amountof a polar solution, typically an aqueous solution or polyethyleneglycol solution that itself contains 10%-40% of surfactant, typicallynonionic surfactant, to bring the composition to 100%.

In another embodiment, the formulation comprising active ingredient andthe above-stated amounts of benzyl alcohol and lecithin organogel isessentially anhydrous and comprises bile salts and essentially no water.The bile salts are present in a percentage of 1-15% w/w in the totalcomposition. These compositions may further contain a surfactant, whichas above, is typically nonionic, which is supplied in powder form. Thepercentage composition of the detergent may be quite high and in therange of 20-60% w/w. In this embodiment, typically, the components ofthe composition—the active ingredient, the lecithin organogel, thebenzyl alcohol and bile salt are “topped off” with the powdered form ofthe surfactant.

In some embodiments, bile salts themselves are an active agent in thatthe compositions are able to dissolve fat deposits due to the action ofthe bile salt. In these compositions, lower limit of lecithin organogelis extended from 25% w/w to 0.5% w/w as a lower limit.

In still another embodiment, in addition to active agent, lecithinorganogel in the range of 25%-70% w/w in benzyl alcohol in theabove-stated range of 0.5-20% of the total, nonionic detergent is mixedwith the remaining ingredients and buffered with a concentrated aqueoussolution to pH 9-11.

In still another embodiment, in the essentially anhydrous compositionsof the invention, the formulation contains an effective amount of activeingredient, 0.5%-70% w/w lecithin organogel, 0.5%-2% w/w of benzylalcohol or alternative alcohol, 1%-15% w/w of bile salt, and a powderedform of nonionic surfactant. This formulation may also be buffered tothe range of pH 9-11.

In still another aspect, the invention is directed to a penetrantcomposition lacking an active agent, but containing the remainingcomponents of the penetrant at concentrations that when mixed with therequisite amount of active agent will result in the formulationsdescribed above.

In other aspects, the invention is directed to delivery of the activeagent either simply to local subdermal locations or systematically to ahuman or non-human animal using the formulations of the invention. Theinvention is also directed to the penetrant itself where its compositionamounts are adjusted to take account of the contribution to the overallcomposition of the active ingredient.

The formulations of the invention share the above-describedcharacteristics regardless of the nature of the active ingredient.However, the choice among penetrants fitting this description and themanner of their application may vary with the nature of what is to beadministered. For example, in administering anesthetics, it is oftenuseful to include epinephrine or other vasoconstrictor which may requireadjustments in administration technique due to the instability ofepinephrine at the high pH that is desirable in administering theanesthetic itself. In the case of volume enhancement using adicarboxylic anhydride, premature hydrolysis of the anhydride must beprevented and thus either an anhydrous composition must be used or theapplication must be done in such a way that the anhydride does not havean opportunity to hydrolyze. That said, compositions with theabove-described characteristics are applicable to a wide range of activeingredients and in a wide variety of applications.

Typically, the subject to be treated with the formulations of theinvention is human, but the use of the penetrant(s) is not limited tohuman use. The transdermal effects are also exerted in other animalsincluding mammals, birds and fish.

In the methods of the invention, the exact procedure for applying theformulation will depend on the nature of the active ingredient. However,as the treatment in general opens the skin to permeation, it isgenerally useful to essentially reseal the area of application byapplying, for example, a composition comprising linoleic acid whichserves this purpose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B show the effectiveness of the formulations of theinvention in removing crow's feet in a subject. FIG. 1A shows thesubject before treatment and FIG. 1B shows the subject 15 minutes aftertreatment.

FIGS. 2A and 2B show the sustained effect of this treatment where thesubject shown in FIG. 1A is shown again in FIG. 2A and in FIG. 2B thesame subject is shown approximately four months after treatment.

FIGS. 3A and 3B show treatment of another subject for crow's feet usingthe formulations of the invention. FIG. 3A shows the subject prior totreatment and FIG. 3B shows the subject 15 minutes after treatment.

FIGS. 4A and 4B show the results of topical treatment with DCA todissolve fat after 12 days. FIG. 4A shows the relevant area before andFIG. 4B shows the relevant area after treatment when 12 days haselapsed.

FIGS. 5A and 5B show the results of treatment of the same subject asFIGS. 4A and 4B, except the “After” depiction is one month subsequent totreatment.

FIGS. 6A-6C show relative performance parameters of treated vs. controlwhere the treated subject is supplied a formulation containing nutrientfactors and metabolism balancing moieties. FIG. 6A shows the relativeenhanced time a subject performing a calf flexion/heel raise exercise isable to perform the exercise before experiencing lactic acid burn. FIG.6B shows the relative time until threshold pain is experienced. FIG. 6Cshows the relative number of repetitions that can be performed intreated vs. untreated controls.

FIG. 7 shows a comparison of performance of treated and untreatedcontrols in performing pushups across 5 sets.

FIGS. 8A and 8B show an overview of a section of the scalp of a subjecttreated with the invention compositions before and after treatmentindicating the treated and untreated areas.

FIGS. 9A and 9B are before and after depictions respectively of hairgrowth in the treated area.

FIGS. 10A and 10B show a comparison of the untreated area before andafter the time period used in the treatment shown in FIGS. 9A and 9B.

FIGS. 11A and 11B show photographs of overall hair growth exhibited byeach of two subjects with concentrations of bimatoprost in the inventionformulations of 0.015% w/w and 0.3% w/w, respectively.

FIGS. 12A and 12B show enlarged views of the results in the subjects ofFIGS. 11A and 11B after seven weeks of treatment.

FIG. 13A-15B are photographs of the toenails of subjects before andafter treatment for onychomycosis. FIG. 13A-15A show toenails of thesubjects prior to treatment and FIG. 13B-15B show the same nails afterthree weeks of treatment twice daily.

FIG. 16A-D are photomicrographs showing the micelle density of variousformulations prepared by different milling procedures.

FIG. 17 is a comparison of micelle density versus pain attenuation usingformulations of lidocaine prepared by different milling procedures.

MODES OF CARRYING OUT THE INVENTION

As noted above, the superior effects achieved by the formulations andmethods of the present invention are attributable to an improvedformulation that enhances delivery of an active agent through the skin.The carrier employs penetrants described in the above citedUS2009/0053290 ('290) and WO2014/209910 ('910)—i.e., benzyl alcohol anda lecithin organogel, but at much higher ratios of lecithin organogel tobenzyl alcohol than in the prior art compositions. The present carriersalso may include a nonionic surfactant which is disclosed to beundesirable in the '910 publication and is described in the '290publication as present only in very low amounts. Applicants have foundthat by employing very high amounts of the lecithin organogel relativeto benzyl alcohol and relative to the weight of the formulation, as wellas in some embodiments providing a combination of a nonionic surfactantand molar excess of a polar gelling agent, the penetration capabilitiesof the resulting formulation and the effective level of delivery of theactive agent can be greatly enhanced. Such a result was completelyunpredictable as it was believed that relatively equal amounts of thebenzyl alcohol and lecithin organogel especially a somewhat higherconcentration of benzyl alcohol than lecithin organogel were responsiblefor the level of penetration achieved by prior art formulations.

In embodiments where a bile salt is added to the combination of benzylalcohol and lecithin organogel in lieu of topping off with an aqueousmedium, micelles that would have been relatively spherical may becomeelongated and worm-like thus permitting superior penetration of thestratum corneum of the epidermis. The worm like formation of themicelles is particularly helpful in accommodating higher molecularweight therapeutic agents. Bile salts are facial amphiphiles and includesalts of taurocholic acid, glycocholic acid, taurochenodeoxycholic acid,glycochenodeoxycholic acid, cholic acid, deoxycholic acid. Otherdetergents are also useful in lieu of bile salts, and include Tween® 80and Span® 80. As noted above, where the bile salt is the activeingredient in the dissolution of fat deposits, lower concentrations ofthe lecithin organogel are included within the scope of theformulations.

The inclusion of these bile salts facilitates the ultradeformability ofmicelles which, in turn, facilitate passage of low and high molecularweight drugs and other active agents such as nucleic acids and proteins.These compositions overcome the skin penetration barrier by squeezingthemselves along the intercellular sealing lipid thereby following thenatural gradient across the stratum corneum. This facilitates a changein membrane composition locally and reversibly when pressed against orattracted to a narrow pore.

In some formulations of the invention, in addition to the above amountsof bile salts, benzyl alcohol, lecithin organogel and active ingredient,the formulations are “topped off” with a powdered nonionic detergent.The pH of such compositions can be determined by taking a small sampleand dissolving it in water to test the appropriate pH. In manyembodiments, the pH is in the range of 8.5-11 or 9-11 or 10-11.

In some formulations, formation of micelles is enhanced by milling. Thelevel of enhancement is determined by the pressure and speed at whichmilling occurs as well as the number of passes through the millingmachine. As the number of passes and the pressure is increased, thelevel of micelle formulation is enhanced as well. In general, increasingthe pressure and increasing the speed of milling enhances the level ofmicelle density. When the ointment milling machine is a Dermamill 100(Blaubrite) marketed by Medisca®, typical speeds include any variationbetween 1 to 100, where 1 is the slowest speed and 100 is the fastestspeed, such as speeds of 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55,60, 65, 70, 75, 80, 85, 90 or 100, or any speed in between. The pressureis selected from 1 to 5, where 1 is the highest pressure and 5 is thelowest pressure. The pressure used can be selected from 1, 2, 3, 4, or5. The number of passes can also be varied, where a pass is completewhen all of the product has passed through the rollers of the machine.Multiple passes, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more passes, arecontemplated in some embodiments. The speed and pressure can be variedfor each pass. For example, a first pass may have a first pressure andfirst speed, while a second (or subsequent) pass may have a secondpressure and second speed, where the second pressure is the same ordifferent from the first pressure and the second speed is the same ordifferent from the first speed. The desired micelle density forparticular formulations can be determined empirically by varying thespeed, pressure and number of passes.

Of course, alternative ointment milling machines could also be used, andcomparable speeds, pressures and numbers of passes are replicated bycomparison to the equivalents on the Dermamill 100. Alternatively,micelle densities can be compared microscopically to assure equivalentresults to those set forth herein. In some embodiments, micelle densityis at least 20% and in many embodiments 30%, 50%, 70%, 80%, or 90% andall levels within this range, as determined by the method described inExample 23 below.

The percentage of active agent in the formulation will depend upon theamount required to be delivered in order to have a useful effect ontreating the disorder. In general, the active ingredient may be presentin the formulation in an amount as low as 0.01% w/w up to about 50% w/w.Typical concentrations include 0.25% w/w, 1% w/w, 5% w/w, 10% w/w, 20%w/w and 30% w/w. Since the required percentage of active ingredient ishighly variable depending on the active agent and depending on thefrequency of administration, as well as the time allotted foradministration for each application, the level of active ingredient maybe varied over a wide range, and is limited only by the necessity forincluding in the formulation aids in penetration of the skin by theactive ingredient.

The formulations of the invention may include only one active agent or acombination of active agents. In the present application, “active agent”or “active ingredient” refers to a compound or drug that is activeagainst the factors or agents that result in the desired therapeutic orother localized systemic effect.

In general, in the present application, “a,” “an,” “one,” and the likeshould be interpreted to mean one or more than one unless it is clearfrom the context that only a single referent is intended. Thus, “anactive ingredient” may refer to one or more such active ingredients.

The formulations of the invention may be prepared in a number of ways.Typically, the components of the formulation are simply mixed togetherin the required amounts. However, it is also desirable in some instancesto, for example, carry out dissolution of an active ingredient and thenadd a separate preparation containing the components aiding the deliveryof the active ingredients in the form of a carrier. The concentrationsof these components in the carrier, then, will be somewhat higher thanthe concentrations required in the final formulation. Thus, ananesthetic such as lidocaine might first be dissolved in alcohol andthen added to a carrier comprising benzyl alcohol, lecithin organogeland optionally a combination of a nonionic surfactant and polar gellingagent, or of ionic detergent and a bile salt. Alternatively some subsetof these components can first be mixed and then “topped off” with theremaining components either simultaneously or sequentially. The precisemanner of preparing the formulation will depend on the choice of activeingredients and the percentages of the remaining components that aredesirable with respect to that active ingredient.

The Nature of the Penetrant

The penetrant formulation is a multi-component mixture whereby theparticular concentrations of the penetration enhancers are informed inpart by the molecular mass of the proposed guest drugs to betransported. The drug delivery system enables the guest molecules tobecome bio-available to the target site within minutes of topicaladministration. The formulations permit the use of minimalconcentrations of guest molecules, as little as 1/1000th ofconcentrations required of alternative processes, while enablingbioactivity and positive clinical outcomes simultaneously.

The formulations comprise mixtures wherein the components interactsynergistically and induce skin permeation enhancements better than thatinduced by the individual components. Synergies between chemicals can beexploited to design potent permeation enhancers that overcome theefficacy limitations of single enhancers. Several embodiments disclosedherein utilize three to five distinct permeation enhancers. (As usedherein “detergent” and “surfactant” are synonymous.)

As noted above, the essential components of the formulations for mostapplications are 25%-70% w/w lecithin organogel and 0.5-20% w/w benzylalcohol or closely related alcohol as well as supplementary componentssuch as detergents, typically nonionic detergents, bile salts, polarsolvents and the like. Each of these is further discussed below:

The lecithin organogel included in the composition is a combination oflecithin with a gelling component, which is typically amphiphilic.Suitable gelling components include, in addition to isopropyl palmitate,ethyl laurate, ethyl myristate and isopropyl myristate. Certainhydrocarbons, such as cyclopentane, cyclooctane, trans-decalin,trans-pinane, n-pentane, n-hexane, n-hexadecane may also be used. Thus,an important permeation agent is a lecithin organogel, wherein thecombination resulting from lecithin and the organic solvent acts as apermeation agent. Lecithin organogels are clear, thermodynamicallystable, viscoelastic, and biocompatible jelly-like phases, chieflycomposed of hydrated phospholipids and appropriate organic liquid. Anexample of a suitable lecithin organogel is lecithin isopropylpalmitate, which is formed when isopropyl palmitate is used to dissolvelecithin. The ratio of lecithin to isopropyl palmitate may be 50:50.Illustrated below in the Examples is a formulation containing soylecithin in combination with isopropyl palmitate; however, otherlecithins could also be used such as egg lecithin or syntheticlecithins. Various esters of long chain fatty acids may also beincluded. Methods for making such lecithin organogels are well known inthe art. In most embodiments, the lecithin organogel is present in thefinal formulation in the range of 25-70% w/w and at intermediatepercentages such as 30% w/w, 40% w/w, 50% w/w, 60% w/w, etc. In thosecompositions used to dissolve fat deposits, to alleviate pain from fatremoval or in anhydrous compositions, the concentration of lecithinorganogel may be as low as 0.5% w/w, 1% w/w, 5% w/w, 10% w/w or 20% w/w.Any suitable percentage within the specified ranges is acceptable aslong as it is compatible with the active agent and the remainingcomponents of the composition.

Lecithin organogels may be in the form of vesicles, microemulsions andmicellar systems. In the form of self-assembled structures, such asvesicles or micelles, they can fuse with the lipid bilayers of thestratum corneum, thereby enhancing partitioning of encapsulated drug, aswell as a disruption of the ordered bilayers structure. An example of aphospholipid-based permeation enhancement agent comprises amicro-emulsion-based organic gel defined as a semi-solid formationhaving an external solvent phase immobilized within the spaces availableof a three-dimensional networked structure. This micro-emulsion-basedorganic gel in liquid phase is characterized by1,2-diacyl-sn-glycero-3-phosphatidyl choline, and an organic solvent,which is at least one of: ethyl laureate, ethyl myristate, isopropylmyristate, isopropyl palmitate; cyclopentane, cyclooctane,trans-decalin, trans-pinane, n-pentane, n-hexane, n-hexadecane, andtripropylamine.

The lecithin organogels are formulated with an additional component toassist in the formation of micelles or vascular structures. In oneapproach, the organogels are formulated with a polar component such aswater, glycerol, ethyleneglycol or formamide, in particular with water.In general, a nonionic detergent such as a poloxamer in aqueous solutionis used to top off. Alternatively, an anhydrous composition may beobtained by using, instead of a polar component, a material such as abile salt. When formulated with bile salts, the micellular nature of thecomposition is altered so that rather than a more or less sphericalvesicular form, the vesicles become wormlike and are able to accommodatelarger guest molecules, as well as penetrate the epidermis moreeffectively. Suitable bile salts include salts of deoxycholic acid,taurocholic acid, glycocholic acid, taurochenodeoxycholic acid,glycochenodeoxycholic acid, cholic acid and the like. Certaindetergents, such as Tween® 80 or Span® 80 may be used as alternatives.The percentage of these components in the anhydrous forms of thecomposition is in the range of 1% w/w-15% w/w. In some embodiments, therange of bile salt content is 2%-6% w/w or 1%-3.5% w/w. In theseessentially anhydrous forms, powdered or micronized nonionic detergentis used to top off, typically in amounts of 20%-60% w/w. In one approachto determine the amount of bile salt, the % is calculated by dividingthe % w/w of lecithin by 10.

An additional required component in the formulations of the invention isan alcohol. Benzyl alcohol is illustrated in the Examples, but in someformulations other alcohols could be included, in particular derivativesof benzyl alcohol which contain substituents on the benzene ring, suchas halo, alkyl and the like. The weight percentage of benzyl or otherrelated alcohol in the final composition is 0.5-20% w/w, and again,intervening percentages such as 1% w/w, 2% w/w, 5% w/w, 7% w/w, 10% w/w,and other intermediate weight percentages are included. Due to thearomatic group present in a permeation enhancement formulation such asbenzyl alcohol, the molecule has a polar end (the alcohol end) and anon-polar end (the benzene end). This enables the agent to dissolve awider variety of drugs and agents. The alcohol concentration issubstantially lower than the concentration of the lecithin organogel inthe composition.

By formulating active ingredients in the presence of at least acombination of a lecithin organogel and a suitable alcohol, especiallybenzyl alcohol where the lecithin organogel is in a ratio ofconcentration at least 10-fold that of the alcohol on a weight basis,superior results are achieved as illustrated in the examples below.

In some embodiments, as noted above, the performance of the formulationsis further improved by including a nonionic detergent and polar gellingagent or including bile salts and a powdered surfactant. In both aqueousand anhydrous forms of the composition, detergents, typically nonionicdetergents are added. In general, the nonionic detergent should bepresent in an amount of at least 2% w/w to 60% w/w. Typically, in thecompositions wherein the formulation is topped off with a polar oraqueous solution containing detergent, the amount of detergent isrelatively low—e.g., 2%-25% w/w, or 5-15% w/w or 7-12% w/w. However, incompositions comprising bile salts that are essentially anhydrous andare topped-off by powdered detergent, relatively higher percentages areusually used—e.g., 20%-60% w/w. The boundaries are not rigid but theabove description indicates the general range.

In some embodiments, the nonionic detergent provides suitable handlingproperties whereby the formulations are gel-like or creams at roomtemperature. To exert this effect, the detergent, typically a poloxamer,is present at a level of at least 9% w/w, preferably at least 12% w/w inpolar formulations. In the anhydrous forms of the compositions, thedetergent is added in powdered or micronized form to bring thecomposition to 100% and higher amounts are used. In compositions withpolar constituents, rather than bile salts, the nonionic detergent isadded as a solution to bring the composition to 100%. If smaller amountsof detergent solutions are needed due to high levels of the remainingcomponents, more concentrated solutions of the nonionic detergent areemployed. Thus, for example, the percent detergent in the solution maybe 10% to 40% or 20% or 30% and intermediate values depending on thepercentages of the other components.

Suitable nonionic detergents include poloxamers such as Pluronic® andany other surfactant characterized by a combination of hydrophilic andhydrophobic moieties. Poloxamers are triblock copolymers of a centralhydrophobic chain of polyoxypropylene flanked by two hydrophilic chainsof polyethyleneoxide. Other nonionic surfactants include long chainalcohols and copolymers of hydrophilic and hydrophobic monomers whereblocks of hydrophilic and hydrophobic portions are used.

Other examples of surfactants include polyoxyethylated castor oilderivatives such as HCO-60 surfactant sold by the HallStar Company;nonoxynol; octoxynol; phenylsulfonate; poloxamers such as those sold byBASF as Pluronic® F68, Pluronic® F127, and Pluronic® L62; polyoleates;Rewopal® HVIO, sodium laurate, sodium lauryl sulfate (sodium dodecylsulfate); sodium oleate; sorbitan dilaurate; sorbitan dioleate; sorbitanmonolaurate such as Span® 20 sold by Sigma-Aldrich; sorbitanmonooleates; sorbitan trilaurate; sorbitan trioleate; sorbitanmonopalmitate such as Span® 40 sold by Sigma-Aldrich; sorbitan stearatesuch as Span® 85 sold by Sigma-Aldrich; polyethylene glycol nonylphenylether such as Synperonic® NP sold by Sigma-Aldrich;p-(1,1,3,3-tetramethylbutyl)-phenyl ether sold as Triton™ X-100 sold bySigma-Aldrich; and polysorbates such as polyoxyethylene (20) sorbitanmonolaurate sold as Tween® 20, polysorbate 40 (polyoxyethylene (20)sorbitan monopalmitate) sold as Tween® 40, polysorbate 60(polyoxyethylene (20) sorbitan monostearate) sold as Tween® 60,polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) sold as Tween®80, and polyoxyethylenesorbitan trioleate sold as Tween® 85 bySigma-Aldrich. The weight percentage range of nonionic surfactant is inthe range of 3% w/w-15% w/w, and again includes intermediate percentagessuch as 5% w/w, 7% w/w, 10% w/w, 12% w/w, and the like.

In the presence of a polar gelling agent, such as water, glycerol,ethyleneglycol or formamide, a micellular structure is also oftenachieved. Typically, the polar agent is in molar excess of the nonionicdetergent. The inclusion of the nonionic detergent/polar gelling agentcombination results in a more viscous and cream-like or gel-likeformulation which is suitable for application directly to the skin. Thisis typical of the aqueous forms of the composition. As noted above, itmay be rather than a polar gelling agent, a bile salt can be used. Inthis case, the detergent is added in solid, powdered form.

In some instances, the formation of micelles is improved by a millingprocedure. In general, more passes and higher pressures favor a higherpercentage of micelles.

In some embodiments other additives are included such as a gellingagent, a dispersing agent and a preservative. An example of a suitablegelling agent is hydroxypropylcellulose, which is generally available ingrades from viscosities of from about 5 cps to about 25,000 cps such asabout 1500 cps. All viscosity measurements are assumed to be made atroom temperature unless otherwise stated. The concentration ofhydroxypropylcellulose may range from about 1% w/w to about 2% w/w ofthe composition. Other gelling agents are known in the art and can beused in place of, or in addition to, hydroxypropylcellulose. An exampleof a suitable dispersing agent is glycerin. Glycerin is typicallyincluded at a concentration from about 5% w/w to about 25% w/w of thecomposition. A preservative may be included at a concentration effectiveto inhibit microbial growth, ultraviolet light and/or oxygen-inducedbreakdown of composition components, and the like. When a preservativeis included, it may range in concentration from about 0.01% w/w to about1.5% w/w of the composition.

Typical components that may also be included in the formulations arefatty acids, terpenes, lipids, and cationic and anionic detergents.

Other solvents and related compounds that may be used in someembodiments include acetamide and derivatives, acetone, n-alkanes (chainlength between 7 and 16), alkanols, diols, short-chain fatty acids,cyclohexyl-1,1-dimethylethanol, dimethyl acetamide, dimethyl formamide,ethanol, ethanol/d-limonene combination, 2-ethyl-1,3-hexanediol,ethoxydiglycol (Transcutol® by Gattefossé, Lyon, France), glycerol,glycols, lauryl chloride, limonene N-methylformamide, 2-phenylethanol,3-phenyl-1-propanol, 3-phenyl-2-propen-1-ol, polyethylene glycol,polyoxyethylene sorbitan monoesters, polypropylene glycol 425, primaryalcohols (tridecanol), 1,2-propane diol, butanediol, C₃-C₆ triols ortheir mixtures and a polar lipid compound selected from C₁₆ or C₁₈monounsaturated alcohol, C₁₆ or C₁₈ branched saturated alcohol and theirmixtures, propylene glycol, sorbitan monolaurate sold as Span® 20 soldby Sigma-Aldrich, squalene, triacetin, trichloroethanol,trifluoroethanol, trimethylene glycol and xylene.

Fatty alcohols, fatty acids, fatty esters, are bilayer fluidizers thatmay be used in some embodiments. Examples of suitable fatty alcoholsinclude aliphatic alcohols, decanol, lauryl alcohol (dodecanol),unolenyl alcohol, nerolidol, 1-nonanol, n-octanol, and oleyl alcohol.Examples of suitable fatty acid esters include butyl acetate, cetyllactate, decyl N,N-dimethylamino acetate, decyl N,N-dimethylaminoisopropionate, diethyleneglycol oleate, diethyl sebacate, diethylsuccinate, diisopropyl sebacate, dodecyl N,N-dimethyamino acetate,dodecyl (N,N-dimethylamino)-butyrate, dodecyl N,N-dimethylaminoisopropionate, dodecyl 2-(dimethyamino) propionate, E0-5-oleyl ether,ethyl acetate, ethylaceto acetate, ethyl propionate, glycerolmonoethers, glycerol monolaurate, glycerol monooleate, glycerolmonolinoleate, isopropyl isostearate, isopropyl linoleate, isopropylmyristate, isopropyl myristate/fatty acid monoglyceride combination,isopropyl palmitate, methyl acetate, methyl caprate, methyl laurate,methyl propionate, methyl valerate, 1-monocaproyl glycerol,monoglycerides (medium chain length), nicotinic esters (benzyl), octylacetate, octyl N,N-dimethylamino acetate, oleyl oleate, n-pentylN-acetylprolinate, propylene glycol monolaurate, sorbitan dilaurate,sorbitan dioleate, sorbitan monolaurate, sorbitan monolaurate, sorbitantrilaurate, sorbitan trioleate, sucrose coconut fatty ester mixtures,sucrose monolaurate, sucrose monooleate, tetradecyl N,N-dimethylaminoacetate. Examples of suitable fatty acid include alkanoic acids, capridacid, diacid, ethyloctadecanoic acid, hexanoic acid, lactic acid, lauricacid, linoelaidic acid, linoleic acid, linolenic acid, neodecanoic acid,oleic acid, palmitic acid, pelargonic acid, propionic acid, and vaccenicacid. Examples of suitable fatty alcohol ethers include α-monoglycerylether, E0-2-oleyl ether, E0-5-oleyl ether, E0-10-oleyl ether, etherderivatives of polyglycerols and alcohols, and(1-O-dodecyl-3-O-methyl-2-0-(2′,3′-dihydroxypropyl)glycerol).

Examples of completing agents that may be used in some embodimentsinclude β- and γ-cyclodextrin complexes, hydroxypropyl methylcellulose(such as Carbopol® 934), liposomes, naphthalene diamide diimide, andnaphthalene diester diimide.

One or more anti-oxidants may be included, such as vitamin C, vitamin E,proanthocyanidin and α-lipoic acid typically in concentrations of0.1%-2.5% w/w.

In some applications, it is desirable to adjust the pH of theformulation to assist in permeation or to adjust the nature of theactive agent and/or of the target compounds in the subject. In someinstances, the pH is adjusted to a level of pH 9-11 or 10-11 which canbe done by providing appropriate buffers or simply adjusting the pH withbase.

In some applications, in particular when the active ingredient includesan anesthetic, epinephrine or an alternate vasoconstrictor, such asphenylephrine or epinephrine sulfate may be included in the formulationif a stabilizing agent is present. Otherwise, the epinephrine should beadministered in tandem since epinephrine is not stable at these pH's.

General Methods of Application

The application method is determined by the nature of the treatment butis, perhaps, less critical than the nature of the formulation itself. Ifthe application is to a skin area, it may be helpful in some instancesto prepare the skin by cleansing or exfoliation. In some instances, itis helpful to adjust the pH of the skin area prior to application of theformulation itself. The application of the formulation may be by simplemassaging onto the skin or by use of devices such as syringes or pumps.Patches could also be used. In some cases, it is helpful to cover thearea of application to prevent evaporation or loss of the formulation.It is especially helpful in the case of application to fingernails ortoenails to do this.

Where the application area is essentially skin as opposed to nails orhair follicles, it is helpful to seal-off the area of applicationsubsequent to supplying the formulation and allowing the penetration tooccur so as to restore the skin barrier. A convenient way to do this isto apply a composition comprising linoleic acid which effectively closesthe entrance pathways that were provided by the penetrants of theinvention. This application, too, is done by straightforward smearingonto the skin area or can be applied more precisely in measured amounts.

Particular techniques for application in connection with specific typesof active ingredients are described in more detail below.

Active Ingredients and Applications

A wide variety of active ingredients may be used in the compositions,including anesthetics, fat removal compounds, nutrients, nonsteroidalanti-inflammatory drugs (NSAIDs) agents for the treatment of migraine,hair growth modulators, antifungal agents, anti-viral agents, vaccinecomponents, tissue volume enhancing compounds, anti-cellulitetherapeutics, wound healing compounds, compounds useful to effectsmoking cessation, agents for prevention of collagen shrinkage, wrinklerelief compounds such as Botox®, skin-lightening compounds, compoundsfor relief of bruising, cannabinoids including cannabidiols for thetreatment of epilepsy, compounds for adipolysis, compounds for thetreatment of hyperhidrosis, acne therapeutics, pigments for skincoloration for medical or cosmetic tattooing, sunscreen compounds,hormones, insulin, corn/callous removers, wart removers, and generallyany therapeutic or prophylactic agent for which transdermal delivery isdesired. As noted above, the delivery may simply effect transport acrossthe skin or nails or hair follicles into a localized subdermal location,such as treatment of nail fungus or modulation of hair growth, or mayeffect systemic delivery such as is desirable in some instances wherevaccines are used. A more detailed description of the formulations inrespect of these active ingredients follows:

In addition to the compositions and formulations of the invention perse, the methods may employ a subsequent treatment with linoleic acid. Astransdermal treatments generally open up the skin barrier, which is,indeed, their purpose, it is useful to seal the area of applicationafter the treatment is finished. Thus, treatment with the formulationmay be followed by treating the skin area with a composition comprisinglinoleic acid to seal off the area of application. The application oflinoleic acid is applicable to any transdermal procedure that results inimpairing the ability of the skin to act as a protective layer. Indeed,most transdermal treatments have this effect as their function is toallow active ingredients to pass through the epidermis to the dermis atleast, and, if systemic administration is achieved, through the dermisitself.

Anesthetics

For administration of anesthetics, typical active ingredients include alocal anesthetic agent or combination of local anesthetic agents. Thelocal anesthetic agent may be one or more of the following: benzocaine,lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, mepivacaine,pramoxine, prilocaine, procaine, chloroprocaine, oxyprocaine,proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine,chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine,levobupivacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, andpharmaceutically acceptable derivatives and bioisosteres thereof.Combinations of anesthetic agents may also be used. The anestheticagent(s) are included in the composition in effective amount(s).Depending on the anesthetic(s) the amounts of anesthetic or combinationis typically in the range of 1% w/w to 50% w/w. The compositions of theinvention provide rapid, penetrating relief that is long lasting. Thepain to be treated can be either traumatic pain and/or inflammatorypain.

In one embodiment, the anesthetic is administered to relieve the painassociated with invasive fat deposit removal. Specific removal of fatdeposits has been attractive for both health and cosmetic reasons. Amongthe methods employed are liposuction and injection of a cytolytic agentfor fat such as deoxycholic acid (DCA). For example, a series of patentsissued or licensed to Kythera Biopharmaceuticals is directed to methodsand compositions for non-surgical removal of localized fat that involvesinjecting compositions containing DCA or a salt thereof. Representativeissued patents are directed to formulation (U.S. Pat. No. 8,367,649);method-of-use (U.S. Pat. Nos. 8,846,066; 7,622,130; 7,754,230;8,298,556); and synthetic DCA (U.S. Pat. No. 7,902,387).

In this aspect of the invention, conventional invasive fat removaltechniques are employed along with administering a pain relievingeffective agent—typically lidocaine or related anestheticstransdermally. In this aspect of the invention, the pain relievingtransdermal composition is applied to the area experiencing painimmediately before, during or immediately after the invasive fat-removalprocedure. Use of certain forms of the penetrants to provide transdermaladministration of anesthetics was described in the above-referencedUS2009/0053290 incorporated herein by reference. However, preferredcompositions employ higher concentrations of the lecithin organogel, oranhydrous forms.

Additional active ingredient(s) may be included in the compositions. Forexample, hydrocortisone or hydrocortisone acetate may be included in anamount ranging from 0.25% w/w to about 0.5% w/w. Menthol, phenol, andterpenoids, e.g., camphor, can be incorporated for cooling pain relief.For example, menthol may be included in an amount ranging from about0.1% w/w to about 1.0% w/w. The active ingredient may itself be analternative such as hydrocortisone and/or menthol instead of a localanesthetic agent.

The compositions containing anesthetics are useful for temporary reliefof pain and itching associated with minor burns, cuts, scrapes, skinirritations, inflammation and rashes due to soaps, detergents orcosmetics, or, as noted above, pain associated with removal of fatdeposits.

In any of the anesthetic compositions, whether anhydrous or not,epinephrine can also be administered and may be helpful. Epinephrine isstable at pH of 2.5-5, and since the compositions for transdermaladministration of anesthetic are preferably at a higher pH—i.e., pH10-11, it may be desirable to administer the epinephrine in tandem withthe transdermal anesthetic. Alternatively, treatment of the epinephrinewith a chelator, such as the iron chelator Desferal® may stabilize theepinephrine sufficiently to include it in the transdermal composition.

The benefits of high pH include higher penetration capability andadjustment of the active form of the fat dissolving compound when theanesthetic is used in conjugation therewith. For example, the pKa of thedeoxycholic acid is 6.58 and the pH of fat is neutral. When deoxycholicacid (DCA) is injected without buffering, it is approximately anequilibrium between the protonated and unprotonated forms. Utilizingformulations with high pH buffering shifts the balance significantly tounprotonated form making the DCA more water soluble and more likely toemulsify fats.

All of the above embodiments achieve several advantages over the priorart. Numbing is achieved very rapidly and is long lasting. For example,numbing may be achieved in about five minutes and the area where thecomposition is applied may remain numb for about 90 minutes. The numbingmay reach a depth of about 25 mm.

The compositions disclosed herein may be delivered by a pump. In oneembodiment, the pump is configured to deliver about 0.15 ml per strokeof the pump as a single dose. Delivering the composition by a pumpallows the amount of the active ingredient needed to be easilycalculated. For example, if the composition includes lidocaine in anamount of about 4% w/w of the composition and about 0.05 ml of lidocaineneeds to be delivered to an area that is about 1 cm² then a pump thatdelivers 0.15 ml is used must be pumped eight times to deliver 1.2ml/cm² of the composition to provide.

One illustrative embodiment of the composition comprises: lidocaine inan amount up to about 5.0% w/w; hydrocortisone in an amount of about0.5% w/w; menthol in an amount of about 1.25% w/w; benzyl alcohol in anamount ranging from about 0.5% to about 10% w/w or about 2.0% w/w;lecithin organogel in an amount that is about 30% to about 60% w/w or45% to about 55% w/w; and a nonionic surfactant in an aqueous solution,in an amount that is the remainder of the composition.

In another embodiment of the composition comprises: lidocaine in anamount of about 4.0% w/w; menthol in an amount of about 1% w/w; benzylalcohol in an amount ranging from about 0.5% to about 10% w/w or about0.9% w/w; lecithin organogel in an amount that is about 30% to about 60%w/w or 45% to about 55% w/w; or about 30% w/w and topped up with 30%Pluronic® in aqueous solution and brought to pH 10.

In another embodiment of the composition comprises: benzocaine in anamount of about 20.0% w/w; menthol in an amount of about 1% w/w; benzylalcohol in an amount ranging from about 0.5% to about 10% w/w or about0.9% w/w; lecithin organogel in an amount that is about 30% to about 60%w/w or 45% to about 55% w/w; or about 30% w/w and topped up with 30%Pluronic® in aqueous solution and brought to pH 10.

In another exemplary embodiment, the composition comprises: benzocainein an amount up to about 5.0% w/w; hydrocortisone in an amount of about0.5% w/w; menthol in an amount of about 1.25% w/w; benzyl alcohol in anamount ranging from about 0.5% to about 10% w/w; lecithin in an organicsolvent in an amount that is about 40% to about 60%; a nonionicsurfactant in an aqueous solution, in an amount that is the remainder ofthe composition.

In another embodiment, the composition comprises: lidocaine in an amountof about 5.0% w/w; menthol in an amount of about 1.25% w/w; benzylalcohol in an amount of about 2.0% w/w; soy lecithin in isopropylpalmitate in an amount ranging from about 45% to about 55% w/w;poloxamer in an aqueous solution in an amount (that is the remainder ofthe composition, and wherein the poloxamer is added to an intermediatemixture of the other constituents and subjected to mechanical shearforce.

As noted above, the inclusion of epinephrine (epi) in the treatment isuseful in many cases, and the exemplary embodiments above may besupplemented by application of, for example, a composition comprisingepinephrine at 0.01% at pH 5. This can be done by applying theformulations sequentially or in layers.

Additional exemplary compositions includebenzocaine+lidocaine+tetracaine (BLT) wherein the benzocaine iscontained at 20% w/w, lidocaine at 6% w/w and tetracaine at 4% w/w (BLT20/6/4). The formulation also contains 0.9% or 2% w/w of benzyl alcoholand 30% w/w lecithin isopropyl palmitate topped up with 30% Pluronic® inaqueous solution, and is brought to pH 10. This can be administered intandem with an epinephrine formulation containing epi at 0.01% w/w,benzyl alcohol at 0.9% or 2% w/w, lecithin isopropyl palmitate at 30%w/w also topped up with 30% Pluronic® in aqueous solution and brought topH 5. The administration is typically sequential, for example,administering the BLT composition first for 15 min. and the epinephrinecomposition second for 15 min. or similar amounts of time.

In another exemplary embodiment, the above described formulation of BLT20/6/4 in benzyl alcohol at 2% w/w and lecithin isopropyl palmitate at30% w/w and is topped up with 30% Pluronic® in aqueous solutionsupplemented with epinephrine at 0.01% w/w preincubated with and/or inthe presence of Desferal®, an iron chelator at 0.1% w/w, and the entirecomposition is brought to pH 10. This can be applied alone for periodsof 10, 15, 20 or 25 minutes residence time on the skin.

In still another exemplary composition, the formulation containing theanesthetic comprises lidocaine at 5% w/w and benzocaine at 20% w/w alongwith benzyl alcohol at either 0.9% or 2% w/w, lecithin isopropylpalmitate at 30% w/w brought to total with 30% w/w Pluronic® in aqueoussolution and pH 10 followed by the above described formulation ofepinephrine at 0.01% w/w at pH 5.

In anhydrous forms of the compositions, similar penetrants and activeingredients in similar amounts are employed, but rather than topping upto 100% with nonionic detergent in aqueous or other polar solution, thecompositions are instead topped up with micronized or other powderedforms of nonionic detergents in the presence of bile salts. Essentially,the syrupy composition which results from the mixture of the alcohol andorganogel along with active ingredient can be blended with a solidcomposition comprising the bile salt and nonionic detergent. Inexemplary compositions, the bile salt is a salt of deoxycholic acid andthe nonionic detergent is Pluronic® or other poloxamer (which is acopolymer of polyethylene glycol and N-polypropylene oxide). Inexemplary compositions, for example, the active ingredient is acombination of benzocaine, lidocaine and tetracaine, the compositioncontains benzyl alcohol and lecithin isopropyl palmitate and is toppedoff with Pluronic® in micronized form and a salt of deoxycholic acid. Inother exemplary compositions the deoxycholic acid salt is replaced bysalts of, for example, taurocholic acid or cholic acid.

In an exemplary embodiment, the BLT 20/6/4 combination in benzyl alcoholat 0.9% w/w and lecithin isopropyl palmitate at 30% w/w is supplementedwith epinephrine at 0.01% w/w and Desferal® at 0.1% w/w and withdeoxycholic acid at 1.5% w/w and Pluronic® in powdered form to bring tothe total amount, adjusted to pH 10. (As this is anhydrous, the pH ismeasured by adding water to the composition before measurement.) In someembodiments, although epinephrine is already included in thecomposition, the above described formulation comprising epinephrine at0.01% w/w and the remaining components brought to pH 5 is administeredseparately.

In summary, the formulations of the invention are suitable foradministering local anesthetics for general relief of pain and inparticular are useful in alleviating the pain associated with localizedfat removal.

Volume Enhancement

In another embodiment of the present invention, enhancement of tissuevolume and quality uses as the active ingredient an acylating agent.Typically, the acylating agent is an anhydride of a dicarboxylic acid.The acylation of protein thus provides a negative charge to the proteinby virtue of liberating the carboxyl group not bound to the protein.Typical suitable anhydrides include maleic anhydride, succinicanhydride, glutaric anhydride, citraconic anhydride, methylsuccinicanhydride, itaconic anhydride, methylglutaric anhydride, phthalicanhydride and the like. Any dicarboxylic anhydride is suitable.Preferred are succinic anhydride and glutaric anhydride. The use ofdicarboxylic acyl chlorides is theoretically possible, but these tend tobe relatively abrasive, and the use of anhydrides is preferred.

The acylating agent useful in enhancing tissue volume can be deliveredin three alternative approaches. In first and second approaches, eitherthe acylating agent is supplied in powdered form and applied to the skinarea covering the tissue to be treated and expanded and this isimmediately followed by treating the skin area with a penetrant thatcauses the acylating agent to be transported through the epidermis andstratum corneum into the tissue or the penetrant is mixed with thepowdered acylating agent immediately before applying the mixture to theskin. The penetrant in this case may, but need not, include a polarmedium such as water. These treatments may be preceded by pretreatingthe skin area with a buffer to neutralize the amino groups on theproteins to be acylated.

Alternatively, in the third approach, the acylating agent can besupplied directly as a formulation in an essentially nonaqueous mediumso that the acylating agent is not deactivated prior to contacting thedesired protein. In this case, also, the skin area may be pretreatedwith buffer to neutralize the amino groups on the protein.

In all cases, the treatment with acylating agent may be followed bytreating the skin area with a composition comprising linoleic acid toseal off the area of application. The application of linoleic acid isactually applicable to any transdermal procedure that results inimpairing the ability of the skin to act as a protective layer. Indeed,most transdermal treatments have this effect as their function is toallow active ingredients to pass through the epidermis to the dermis atleast, and, if systemic administration is achieved, through the dermisitself.

Because the acylating agents of the invention are anhydrides, prolongedcontact with formulations that have an aqueous or polar component wouldinactivate the acylating agent by hydrolysis. Therefore, either anessentially anhydrous composition should be used as a penetrant whichwould permit inclusion of the acylating agent in the formulation to beadministered or the acylating agent is mixed with the compositioncontaining the penetrants immediately prior to application to the skin.In still another alternative, the acylating agent may be applied to theskin in dry form and the penetrating composition added immediatelythereafter. These last two approaches are applicable either to thecompositions of penetrants that are polar in nature or to those that areessentially anhydrous in nature. However, if the penetrationcompositions are polar or aqueous in nature, use of these latter twoapproaches is essentially mandated.

However the acylating agents are applied and allowed to penetrate, theskin may be pretreated by cleansing and exfoliation and, preferablypre-buffered to appropriately pH 8.5-11, preferably 10-11. Theformulation of the invention is then applied using one of the threemethods set forth above as appropriate. The formulation is left incontact with the skin for 10-40 minutes or any appropriate time,preferably 25-30 minutes. Optionally, then, the treatment may beconcluded by treating the affected area by a composition comprisinglinoleic acid. The linoleic acid is applied in an aqueous or nonaqueoussolution at a concentration of 25-95% w/w. In some cases, the linoleicacid can be applied as an extract of a plant that contains it. Theapplication of linoleic acid to rebuild the stratum corneum barrier canbe achieved, therefore, using extracts of sunflower seeds, kukui nutoil, and the like.

A particular sequence that illustrates the method of the invention is asfollows:

(i) Local exfoliation is performed to enhance penetration. This can bedone by tape stripping, mechanical abrasives, chemical exfoliation andthe like. While by no means required, it is not excluded to employpenetration enhancement such as micro-needling, ultrasonic energy,iontophoresis, electroporation and the like.

(ii) The penetrant formulation alone is applied to the target sitebuffered to about pH 8.5-11.

(iii) After a 15 min. delay, it is wiped off.

(iv) The penetrant formulation combined with glutaric anhydride isapplied at the target site, buffered to about pH 8.5-11.

(v) After a 15 min. delay, this is wiped off.

The previous illustrative procedure is merely illustrative and, as notedabove, there are several ways that the penetrant composition containingthe acylating agent can be administered—the composition itself may beanhydrous and/or the time delay between contact of the acylating agentwith the penetrating composition is sufficiently short that evenwater-containing penetrants are useable.

In the final formulation, the percentage of acylating agent in theformulation will depend upon the amount required to be delivered inorder to have a useful effect in enhancing tissue volume. In general,the active ingredient may be present in the formulation in an amount aslow as 0.25% w/w up to about 50% w/w. Typical concentrations include0.25% w/w, 1% w/w, 5% w/w, 10% w/w, 20% w/w and 30% w/w. Since therequired percentage of acylating agent is variable depending on thechoice of such agent and depending on the frequency of administration,as well as the time allotted for administration for each application,the level of active ingredient may be varied over a wide range, and islimited only by the necessity for including in the formulation aids inpenetration of the skin by the active ingredient.

In addition to, or in lieu of, the acylating agent as an activeingredient, inhibitors of hyaluronidase and/or enhancers of HA synthasemay be included as active ingredients. Known enhancers of HA synthaseare the retinoids such as retinol, retinaldehyde and retinoic acid.Known inhibitors of hyaluronidase include flavonoids and otherpolyphenols, alkaloids, terpenoids, and anti-inflammatory drugs.Flavonoids include anthocyanins, flavan-4-ols, flavones and flavanols aswell as condensed tannins or proanthocyanidins. These include, forexample, resveratrol which is a recently publicized component of redwine.

The balance of HA synthase and hyaluronidase is necessary to restore thebalance which provides sufficient moisture in the dermal water reservoirwhich allows water to escape through the epidermis when skin dries, asfor example, through aging or solar exposure. In addition to thebalancing of the concentration of HA, providing a protective layer oflinoleic acid also prevents unwanted loss of water from the dermalreservoir.

Additional active ingredient(s) may be included in the composition. Forexample, hydrocortisone or hydrocortisone acetate may be included in anamount ranging from 0.25% w/w to about 0.5% w/w. Menthol, phenol, andterpenoids, e.g., camphor, can be incorporated for cooling pain relief.For example, menthol may be included in an amount ranging from about0.1% w/w to about 1.0% w/w. Antioxidants and/or preservatives may alsobe included.

Some exemplary formulations include an acylating agent; benzyl alcohol;lecithin; an organic solvent that is at least one of ethyl laurate,ethyl myristate, isopropyl myristate and isopropyl palmitate; nonionicsurface acting agent; and a polar agent that is at least one of water,glycerol, ethylene glycol, formamide and hydroxyl-propylcellulose or inthe alternative to the polar agent, one or more bile salts.

In one embodiment, the composition comprises: glutaric anhydride in anamount up to about 5.0% w/w; hydrocortisone in an amount of about 0.5%w/w; menthol in an amount of about 1.25% w/w; benzyl alcohol in anamount ranging from about 0.5% to about 10% w/w or about 2.0% w/w;lecithin organogel in an amount that is about 30% to about 60% w/w or45% to about 55% w/w; and a nonionic surfactant in a bile salt, in anamount that is the remainder of the composition.

In another exemplary embodiment, the composition comprises: succinicanhydride in an amount up to about 5.0% w/w; hydrocortisone in an amountof about 0.5% w/w; menthol in an amount of about 1.25% w/w; benzylalcohol in an amount ranging from about 0.5% to about 10% w/w; lecithinin an organic solvent in an amount that is about 40% to about 60%; anonionic surfactant in an aqueous solution, in an amount that is theremainder of the composition.

In another embodiment, the composition comprises: succinic anhydride inan amount of about 10.0% w/w; menthol in an amount of about 1.25% w/w;benzyl alcohol in an amount of about 2.0% w/w; soy lecithin in isopropylpalmitate in an amount ranging from about 45% w/w to about 55% w/w;poloxamer in an aqueous solution in an amount (that is the remainder ofthe composition, and wherein the poloxamer is added to an intermediatemixture of the other constituents and subjected to mechanical shearforce.

Formulations for Use to Dissolve Fat Noninvasively

In another embodiment, the essential components of the formulation areat least one active ingredient that is capable of dissolving fat alongwith suitable penetrants that will transduce the ingredients across theskin and into the fat deposit. Suitable fat-dissolving removing activeingredients include deoxycholic acid (DCA) and other bile saltsincluding salts of taurocholic acid, glycocholic acid,taurochenodeoxycholic acid, glycochenodeoxycholic acid, and cholic acid.Certain detergents such as Tween® 80 and Span® 80 are also effective.

As to the penetrant, a particularly preferred penetrant includescombinations of benzyl alcohol and a lecithin organogel. In someembodiments the formulation also includes a nonionic surfactant. Thelevel of benzyl alcohol is present in the range of 1%-20% by weight(w/w); the lecithin organogel in the range of 0.5%-70% w/w and thenonionic detergent and its counterbalancing polar solvent in the rangeof 0.10%-30% w/w. Specifically, the compositions described in the abovecited US2009/0053290 incorporated herein by reference and PCTpublication WO2014/209910, incorporated herein by reference are suitablefor use in this application. It may be preferred, however, to use higherpercentages of lecithin organogel and lower percentages of the benzylalcohol component. The lecithin organogel may be present in amounts suchas 5-60% w/w, 10-55% w/w, 20-40% w/w and intermediate ranges.

Thus, the invention includes formulations and methods for directlyeffecting diminution of local deposits of fat by administering at leastone fat-dissolving compound in a composition comprising penetrants thatpermit transport of the fat-dissolving compound through the skin andinto the fat deposit.

Applicants have observed that the results obtained by applying the fatdissolving compound topically and permitting transdermal conduction tothe fatty deposit results in superior outcomes as compared to injectionof comparable compounds. While not intending to be bound by any theory,it is believed that injection delivers a bolus of high concentrationthat is not allowed to distribute readily over the deposit. On the otherhand, transdermal delivery is comparable to drizzling or soaking andthus permits a more even spread of similar concentrations of the fatdissolving compound throughout the deposit. When the fat cells areflooded, as by using injection with DCA for example, this inducesadipocytolysis in a concentrated area. DCA also has a short half-lifewhich is difficult to measure but is considered generally less than 30minutes. Also, clear disadvantages of injection as compared to topicaladministration include adverse events associated with injection itself,and pain caused simply by the high concentration of DCA in a localizedarea. Adverse events associated with injection itself include side pain,swelling, numbness, bruising, erythema and induration. In clinicalstudies of injectable DCA, these adverse events were observed in 59% ofsubjects receiving placebo by injection and 95% of subjects receivingthe current commercial dose of DCA.

This demonstrates that fat dissolving compounds such as DCA producesignificant pain associated with the active ingredient over and abovephysical pain due to injection. This is illustrated by published data inan article by Renzi, et al., Brit J Dermatol (2014) 170:445-453 whichshowed that of subjects administered a placebo by injection, 47% of themexperienced mild pain, 11% experienced moderate pain, and only 1%experienced severe pain. On the other hand, of all subjects injected DCAat the commercial dose, 30% experienced mild pain, 36% experiencedmoderate pain, and 27% experienced severe pain.

Thus, as described above, a particular application for supplying localanesthetic is to relieve any pain caused by the dissolution of fatwhether the dissolution is provided by conventional methods such asinjection or by the above-described method of transdermal transport.That said, the desirability of anesthetic treatment is much greater forthe injection method; the discomfort caused by DCA per se is morechronic and low level than acute and excruciating.

Supplemental Nutrition

In another embodiment, nutrients are supplied transdermally. There aremany occasions in which the formulations of the invention are useful.For athletes, the formulations can deliver to tired muscles sufficientamounts of a neutralizing agent for lactic acid, such as sodiumbicarbonate, to relieve the burning sensation felt by the athlete due tothe buildup of lactic acid. This permits the athlete to continue toperform at optimum level for longer periods of time. In addition,athletes or others “working out” are expending high amounts of energyand are in need of energy generation especially in those areas of theirmusculature that are involved in performing workouts and, therefore,need to consume large numbers of calories. These nutrients can besupplied directly rather than requiring oral ingestion which iscounterproductive and relatively slow.

While athletes or individuals “working out” are used as illustrationsherein, it is apparent that any individual subjected to tasks whichrequire physical exertion would benefit from the compositions andmethods of the invention. This includes, for example, constructionworkers, farm laborers, other laborers, soldiers and sailors or evenindividuals who ordinarily are not engaged in physical labor but onoccasion are called upon to do so.

Emergency medical treatment of individuals requiring, for example, bloodbalancing agents including electrolytes and readily-metabolizednutrients, such as glucose, that would otherwise be administeredintravenously can instead be non-invasively treated by massaging theformulation through the skin and thus permitting systemic delivery sothat levels in the bloodstream are altered. Circumstances when this isdesirable are well known, including emergency medication andpostoperative treatments.

In addition to these applications, it has been noted that theadministration of nutrients according to the invention also assuagesfeelings of hunger. Therefore, the formulations of the invention andmethods of the invention are useful in promoting weight loss as thecaloric intake required to assuage feelings of hunger is lower than thatordinarily experienced by consuming food conventionally. Thus, inaddition to individuals requiring extra calories or metabolic balancersbecause of exertion and in addition to those unable to feed themselvesorally, suitable subjects for the methods of the invention includeindividuals seeking to control their caloric intake in order to adjusttheir weight. In view of the generally acknowledged obesity epidemic inthe United States in particular, this is an important group of subjectsbenefiting from the methods of the invention.

It is clear that the nature of the desired ingredients will varydepending on the object of the administration. Simple nutrients such asamino acids, glucose, fructose, simple fats, various vitamins, cofactorsand antioxidants as well as somewhat more complex foodstuffs can beadministered as well as neutralizing agents, depending on the need.

Exemplary active ingredients for athletic performance includebeta-alanine, sodium bicarbonate, L-carnitine, adenosine triphosphate,dextrose, creatine monohydrate, beta-hydroxy-beta-methylbutyrate (HMB),branched chain amino acids (leucine, isoleucine, valine), glutathione,sodium phosphate, and caffeine.

Exemplary active ingredients for medical nutrition include amino acids,dextrose, lipids, Na⁺, K⁺, Ca²⁺, Mg²⁺, acetate, Cl—, P, multivitamin,and trace elements.

Exemplary active ingredients for weight loss include conjugated linoleicacids, ephedra, caffeine, and salicin.

In applying the formulations of the invention, the formulation itself issimply placed on the skin and spread across the surface and/or massagedto aid in penetration. The amount of formulation used is typicallysufficient to cover a desired surface area. In some embodiments, aprotective cover is placed over the formulation once it is applied andleft in place for a suitable amount of time, i.e., 5 minutes, 10minutes, 20 minutes or more; in some embodiments an hour or two. Theprotective cover can simply be a bandage including a bandage suppliedwith a cover that is impermeable to moisture. This essentially locks inthe contact of the formulation to the skin and prevents distortion ofthe formulation by evaporation in some cases.

The schedule of application is dependent on the nature of the treatmentbeing administered. Repeated application is often desirable, forexample, during intermittent types of exercise. Alternatively, theformulation may be left in place, preferably covered during athleticperformance. Application to supply nutrients to patients may also be forprolonged periods of time.

The composition may be applied to the skin using standard procedures forapplication such as a brush, a syringe, a gauze pad, a dropper, or anyconvenient applicator. More complex application methods, including theuse of delivery devices, may also be used, but are not required.

It has surprisingly been found that using the formulations and methodsof the present invention, nutrients can be supplied in effective amountstransdermally either preferentially to a desired area or systemically.Other agents which may be helpful in maintaining appropriate metabolicbalance, for example, in muscles, can also be successfully administeredin this manner. Thus, the need for oral administration, intravenous orother invasive administration of such active ingredients is obviated.

Hair Growth Modulation

In another embodiment, the active ingredient is any compound or materialthat is a hair growth modulator.

A number of compounds or compositions that stimulate hair growth areknown in the art. Prominent among these are minoxidil which is of theformula

which has been shown at some level to be effective on topical treatment.However, the success rate for such treatments is minimal and it has notbeen particularly successful in reversing the alopecia caused bychemotherapy. By administering minoxidil in the formulations of theinvention, a higher level of effectiveness for all forms of hair loss orinadequate hair growth can be achieved.

Another agent that has been found to stimulate hair growth is aprostaglandin analog with the generic name bimatoprost. This has theformula:

This compound has been used to restore eyelashes subsequent tochemotherapy. It has been marketed under the tradename Lumigan® and alsoas a cosmetic formulation under the name Latisse®. The effectiveness ofthis compound is also greatly improved by the formulations of theinvention. Other analogs include latanoprost, travoprost andunoprostone.

Another compound known to stimulate hair growth is a retinoid with thegeneric name tretinoin. It is all-trans retinoic acid and has beenmarketed under a number of brand names, including Renova™, RetinA®,Avita®, and many others.

Another approach to providing active agents for hair growth stimulationtakes advantage of compositions containing extracts of plant stem cells.These extracts are believed to stimulate the endogenous senescent stemcells present at the basis of the hair follicle—i.e., the dermalpapilla. A particular lytic extract prepared from a cell line obtainedby culturing stem cells derived from the tree Argania spinosa knowncommercially as PhytoCellTec™ Argan has been used generally to stimulatesenescent stem cells that produce fibroblasts in vitro. The use of thesecompositions to reduce wrinkles is described by Schmid, D., et al.(Mibelle Biochemistry, Switzerland (2008). Applicants have now foundthat these extracts reverse the senescence of stem cells of the dermalpapilla responsible for hair growth.

In addition to these, it is understood by applicants that certain otherprostaglandins besides the analog bimatoprost also stimulate hairgrowth. These include PGE₂ and PGF_(2a).

An additional agent that is known to stimulate hair growth, especiallyin combination with bimatoprost is cyclosporin.

Alternatively, if inhibition of hair growth is desired, certainprostaglandins are known to effect hair growth inhibition. These includePGD₂ and its metabolite 15dPGJ₂. If hair growth inhibition is desired,these ingredients as active agents may be included in lieu of thestimulating compounds and preparations. The general method ofapplication is the same, but the inhibition of hair growth would includeapplication to areas that would not necessarily be subject todesirability of hair growth stimulation. Thus, for hair growthstimulation, application to the scalp or, in the case of men, facialareas, is indicated. Stimulation of eyelash growth involves applicationto the eyelid. For inhibition of hair growth, in women, for example,application to the face might also be desirable as well as to the limbsand underarms. The area of application is, of course, strictly speakingthe decision of the subject and the treating practitioner.

The effectiveness of these and other hair growth modulating agents isgreatly enhanced by employing them in the formulations of the inventionwhich have superior penetrating qualities. In some embodiments,combinations of one or more such agents can be employed in the sameformulation or sequentially. Thus, combinations of minoxidil withtretinoin or of tretinoin with bimatoprost or of either of these withstem cell extracts derived from apples or other plant tissue may beemployed.

In addition to direct application to the skin, for example, the scalp oreyelids or facial skin, a technique proposed by RepliCel™ Life Sciencesusing a punch biopsy technique to harvest hair follicles from a scalpcan be employed in combination with the formulations of the inventionapplied directly. In this technique, the punch biopsy harvests hairfollicles followed by dissection of the dermal papilla and inversion ofthe dermal sheath cup. The dermal papilla is discarded and the dermalsheath cup is cultured yielding dermal cup cells in large numbers. Thecells are then re-injected into the donor's scalp. These cellsthemselves could also be used as active ingredients in the formulationsof the invention.

Other invasive methods are also known which can be used in combinationwith the formulations of the invention. In all cases where stem cellsderived from the subject in question are cultured outside the subject,the cells are suitable as active ingredients in the formulations of theinvention.

The compositions may be adjusted to pH 10-11 in some embodiments.

In one embodiment, the composition comprises: bimatoprost in an amountup to about 5.0% w/w; benzyl alcohol in an amount ranging from about0.5% to about 10% w/w or about 2.0% w/w; lecithin organogel in an amountthat is about 30% to about 60% w/w or 45% to about 55% w/w; and anonionic surfactant in an aqueous solution, in an amount that is theremainder of the composition.

In another exemplary embodiment, the composition comprises: minoxidil inan amount up to about 5.0% w/w; benzyl alcohol in an amount ranging fromabout 0.5% to about 10% w/w; lecithin in an organic solvent in an amountthat is about 40% to about 60%; a nonionic surfactant in an aqueoussolution, in an amount that is the remainder of the composition.

In another embodiment, the composition comprises: tretinoin in an amountof about 5.0% w/w; benzyl alcohol in an amount of about 2.0% w/w; soylecithin in isopropyl palmitate in an amount ranging from about 45% toabout 55% w/w; poloxamer in an aqueous solution in an amount (that isthe remainder of the composition, and wherein the poloxamer is added toan intermediate mixture of the other constituents and subjected tomechanical shear force.

In essentially anhydrous forms of the compositions, similar penetrantsand active ingredients in similar amounts are employed, but rather thantopping up to 100% with nonionic detergent in aqueous or other polarsolution, the compositions are instead topped up with micronized orother powdered forms of nonionic detergents in the presence of bilesalts. Essentially, the syrupy composition which results from themixture of the alcohol and organogel along with active ingredient can beblended with a solid composition comprising the bile salt and nonionicdetergent. In exemplary compositions, the bile salt is a salt ofdeoxycholic acid and the nonionic detergent is Pluronic® or otherpoloxamer (which is a copolymer of polyethylene glycol andN-polypropylene oxide). In exemplary compositions, for example, theactive ingredient is a combination of minoxidil and tretinoin, thecomposition contains benzyl alcohol and lecithin isopropyl palmitate andis topped off with Pluronic® in micronized form and a salt ofdeoxycholic acid. In other exemplary compositions the deoxycholic acidsalt is replaced by salts of, for example, taurocholic acid or cholicacid.

In an exemplary embodiment, PhytoCellTec™ Argan at 5% w/w in combinationin benzyl alcohol at 0.9% w/w and lecithin isopropyl palmitate at 30%w/w is supplemented with deoxycholic acid at 1.5% w/w and Pluronic® inpowdered form to bring to the total amount, adjusted to pH 10. (As thisis anhydrous, the pH is measured by adding water to the compositionbefore measurement.)

As noted above, the inclusion of epinephrine (epi) or othervasoconstrictor in the treatment is useful in many cases, and theexemplary embodiments above may be supplemented by application of, forexample, a composition comprising epinephrine at 0.01% at pH 5. This canbe done by applying the formulations sequentially or in layers.

The compositions disclosed herein may be delivered by a pump. In oneembodiment, the pump is configured to deliver about 0.15 ml per strokeof the pump as a single dose. Delivering the composition by a pumpallows the amount of the active ingredient needed to be easilycalculated. For example, if the composition includes minoxidil in anamount of about 4% w/w of the composition and about 0.05 ml of minoxidilneeds to be delivered to an area that is about 1 cm² then a pump thatdelivers 0.15 ml is used must be pumped eight times to deliver 1.2ml/cm² of the composition to provide.

Nail Disorders and Fungal Infections Generally

It has surprisingly been found that using the formulations and methodsof the present invention, clearing of disorders of the nail and nail bedcan be effected in three weeks or less, as shown in Example 18 below.This represents essentially a 10-fold improvement over currentlyavailable compositions designed for topical treatment of thesedisorders. Without intending to be bound by any theory, applicantsbelieve that the improvement is due to the enhanced ability of theformulations of the invention to permit penetration of the fingernail ortoenail and the underlying skin by the active ingredient or ingredientsin the formulations, so as to effect systemic delivery. Improvementshave also been made in conducting the method of applying theseformulations.

There are a number of commonly experienced disorders of the nail andnail bed that are treatable by the formulations and methods of theinvention. Prominent among these is onychomycosis which is the mostcommon of such conditions in adults. It is estimated that in NorthAmerica, the incidence falls between 2-13% of the population. It isgreater in older adults and up to 90% of elderly may be affected. It isa fungal infection often associated with other conditions. In thedevelopment of this condition, the nail becomes thicker and changes to ayellowish brown and may collect foul smelling debris under the nail.

Another common condition susceptible to treatment by the formulationsand methods of the invention is psoriasis. This is a non-contagiousinflammatory disease. Nail psoriasis is characterized by pitting of thefingernails or toenails and the affected nails may thicken, yellow orcrumble. Sometimes the skin around the nail is also inflamed. Otherdiseases of the nail include inflammatory conditions, i.e., onychia oronychodystrophy which is generically malformation or discoloration inthe nails due to illness or injury or subungual hematoma or koilonychiawhere the outer surfaces of the nail are concave.

In addition to nail and nail bed disorders per se, also suitable fortreatment by the formulations and methods of the invention areconditions of the skin that can be treated topically. These conditionsare often also fungal infections. Thus, among other symptomologies thatcan be treated are those associated with athlete's foot and jock itch.In addition, in some cases, psoriasis exhibited on skin areas generallyis treatable using the same formulations by topical treatment of thesecompositions. Although these are conditions of the skin per se, in orderto address them effectively, it is helpful to have the active ingredientin the formulation penetrate through the skin to attack the causativeagents contained either within the dermis or immediately below.

It is evident that in view of the variety of types of nail, nail bed andskin disorders, the nature of the active ingredients may vary over awide range. In some cases, the underlying cause is not understood andthe subject may be benefited by providing, for example, vitamins,cofactors or nutritional aids to the localized region under the nail oron the skin. These may be useful supplements in any case.

Since a large percentage of nail, nail bed and superficial skindisorders are caused by fungi, including yeast, particularly usefulactive agents are antifungal agents such as medomycin, nystatin andamphotericin B, various imidazole compounds, such as miconazole,ketoconazole, clotrimazole, exonazole, bifonazole, butoconazole,fenticonazole, isoconazole, oxiconazole, sertaconazole, suconazole, andtioconazole; triazole compounds such as fluconazole, itraconazole,ravuconazole, posaconazole, and voriconazole and also the presentlymarketed oxaborole antifungal, tavaborole. Also useful are allyl aminecompounds such as terbinafine, amorolfine, naftifine, and butenafine andthe like. The choice of the active agent is arbitrary and any antifungalagent including those active against yeast should be effective for thoseconditions that are characterized by fungal infections. Exemplary agentsalso include echinocandin compounds such as anidulafungin, caspfungin,and micafungin; and other antifungal drugs such as ciclopirox,flucytosine, griseofulvin, gentian violet, haloprogin, tolnaftate,efinaconazole and undecylenic acid. Other types of drugs are more usefulfor other conditions of the nail and nail bed such as psoriasis andhematomas. For example, pharmaceutical agents may be effective such asanti-inflammatories, antibiotics, and anesthetics, vitamins and thelike. Other agents that may be included in the formulation includeantioxidants and moistening agents.

In applying the formulations of the invention for nail disorders, theformulation itself is simply placed on the nail and spread across thesurface. The amount of formulation used is typically sufficient to coverthe surface of the nail and the nail is left in contact with theformulation for at least 5 minutes, but preferably 10 minutes, 30minutes or more. In some embodiments, a protective cover is placed overthe formulation once it is applied and left in place for a suitableamount of time, i.e., 5 minutes, 10 minutes, 20 minutes or more; in someembodiments an hour or two. The protective cover can simply be aband-aid or other type of bandage including a bandage supplied with acover that is impermeable to moisture. This essentially locks in thecontact of the formulation to the nail and prevents distortion of theformulation by evaporation in some cases. The water content of the nailplate varies between 7% and 18% by weight. While somewhatcounterintuitive in view of its hardness, the nail plate is about1,000-fold more permeable to water than is skin. Due to its porosity,the nail plate can be rapidly hydrated and dehydrated. Occlusion of thenail alters the barrier properties of the nail. Occlusion of the nailplate for less than one hour results in distention of intercellularspaces through which polar and nonpolar substances can permeate morereadily. Occlusion can be accomplished through the application oflacquer-like agents, band-aids, and the use of impermeable latex fingercots and these are best removed within an hour to prevent secondaryinflammation.

Application of the formulations to treated superficial skin conditionssuch as athlete's foot, psoriasis and jock itch, similar techniquesapply, often employing massaging the formulation into the affected area.It may be desirable in this case to apply a covering to the affected andtreated area as well. The application times and intervals depend, ofcourse, on the severity of the condition, the nature of the conditionand the judgment of the practitioner.

In some typical protocols, for either nail or skin treatment, theapplication of the formulation is done as needed—typically one, two orthree times daily and more frequently if needed. Repeated applicationsare also included within short timeframes such as three half-hourapplications over the course of an afternoon. As above, the treatmentschedule is dependent on the severity of the condition and the judgmentof the practitioner treating the disorder. The treatment may be repeatedover a substantial period of time, such as one week, two weeks or threeweeks or more and the treatment may be done on a regular basis, such asdaily, twice daily or once every two days, but may be staggered on anirregular basis as well—e.g., the first treatment on Day 1, a secondtreatment on Day 3, a third treatment on Day 4, a fourth treatment onDay 6, where the series does not exhibit any particular order. It shouldbe emphasized that systemic delivery of the active agent is achieved.

In addition the regular debridement of the infected nail beforeapplication of the formulation gives an additional advantage of thinningthe nail plate, thereby, further enhancing penetration.

In addition, nail growth is encouraged by supplying appropriatenutrients in the context of the penetrant of the invention. Variousnutritional agents are supplied in this manner, including biotin,cystine, thiamine, pantothenic acid (Vitamin B5) and other suitablenutrients. The method of application and treatment is similar to that asdescribed above for antifungal treatment.

The composition may be applied to the nail using standard procedures forapplication such as a brush, a syringe, a gauze pad, a dropper, or anyconvenient applicator. More complex application methods, including theuse of delivery devices, may also be used, but are not required.

Antivirals

The formulations of the invention are also useful in deliveringantiviral compounds. Some antiviral infections are superficial, but insome instances, systemic infection can also be beneficially treated bythe penetrating formulations of the invention.

A number of antiviral agents are available, such as acyclovir(Zovirax®), valacyclovir (Valtrex®), famciclovir (Famvir®),penciclovir)(Denavir®, foscarnet, cidofovir and docosanol) (Abreva®.Most antiviral drugs are administered orally, but in many cases exhibitpoor bioavailability due to “first-pass” metabolism, with only about 15%to 30% of the oral formulation being absorbed. Penciclovir (1%Denavir®), docosanol (10% Abreva®), and acyclovir (3% Zovirax®) areavailable as topical creams, which circumvents systemic metabolism;however, these formulations may not be adequately penetrating and aredesigned to treat superficial infections.

Penciclovir (Denavir® topical cream 1%) is claimed to “penetrate theskin to deliver penciclovir directly to the site of infection.” Due toits high molecular weight, penciclovir is unlikely to breach intact skinand the stratum corneum barrier without chemical permeation enhancers inthe formulation. It has been demonstrated to be more effective againstHSV-infected cells than alternatives, such as Abreva®.

Abreva® is the only over-the-counter (OTC) topical dermal antiviralagent in the United States. The active agent in Abreva® is 10%docosanol, also known as behenyl alcohol. It is a saturated alcohol with22 carbon atoms and used in the cosmetic trade as an emollient,emulsifier and thickener and has been approved by the Food and DrugAgency (FDA) as a pharmaceutical antiviral agent with claims that itreduces the duration of cold sores caused by the herpes simplex virus.

Corticosteroids have also been combined with antivirals in attempts todecrease the signs of inflammation, i.e., hyperemia, pain, edema andlocalized increase in skin temperature.

Methods of application of these antiviral agents, similar to those ofother active ingredients, are typically by simple topical application,through massage or patch or by pumping devices.

Applications of the Invention Formulations and Methods

As is apparent from the discussion above, the penetrants of theinvention have wide application and are applicable to a number of drugdelivery scenarios and can be adapted to the administration of a widevariety of active components. The extent of delivery is dependent on theapplication—simple transdermal transmission to a site of action as inthe case of local anesthetics, treatment of fingernails or toenails, orvolume and texture enhancement of tissue are examples of local delivery.On the other hand, delivery of nutrients and in some cases antiviralagents and anti-infective agents as well as cannabinoids and painkillers such as NSAIDs can be systemic. The particular choice offormulation within the scope of the invention and the level of activeingredient, the time of application, the frequency of application, andthe dosage levels overall are within the judgment of the practitionerand within the skill of the art.

Notably, local anesthetics can readily be delivered using theformulations of the invention by simple application to the skin. In thiscase, the use of epinephrine is beneficial as is the use of highpH—e.g., pH 9-11. Because epinephrine is not stable at such high pH's,either it should be delivered separately in tandem with the delivery ofthe anesthetic itself in a composition of suitable pH, or it may bestabilized by adding an appropriate stabilizing agent such as Desferal®in the context of the anesthetic composition itself.

In general, the invention is directed to administering a localanesthetic to a subject transdermally and a formulation which containsan effective amount of anesthetic along with 25%-70% w/w or 30%-60% w/wor 30%-40% w/w of lecithin organogel typically wherein the lecithinorganogel comprises soy lecithin in combination with isopropyl palmitateor isopropyl myristate and benzyl alcohol in the range of 0.5%-20% w/wor 0.9%-2% w/w benzyl alcohol optionally including 1%-5% w/w or 2%-4%w/w menthol wherein the composition is topped off with a polar solution,typically an aqueous solution comprising 15%-50% w/w or 20%-40% w/w or20%-30% w/w poloxamer, typically Pluronic® or alternatively may be ananhydrous composition comprising bile salts such as deoxycholic acid orsodium deoxycholate in the range of 4%-8% w/w, typically 6% w/w and theremainder of the composition powdered nonionic detergent, typicallyPluronic®. The pH of the compositions is adjusted to 9-11, typically10-11. The formulations are applied to the desired area of the skin andmay be covered, for example, with Saran™ wrap for a suitable amount oftime. Following the treatment, the skin can be repaired by applying acomposition comprising linoleic acid.

Similar formulations as described above are used wherein the activecomponent is an antifungal or a combination of antifungals, a nutrientor combination of nutrients, a dicarboxylic anhydride, or a hair growthmodulator. The location for application will, of course, depend on theuse—typically antifungals are applied to fingernails or toenails; hairgrowth modulators applied to the scalp, dicarboxylic acid anhydrides orinhibitors of hyaluronidase or enhancers of hyaluronic acid synthase toareas of the skin or tissue where enhanced volume or quality is desired,and nutrients to, for example, muscle tissue.

In the case of the use of dicarboxylic anhydrides for tissue volumeenhancement, again, high pH is indicated and the composition must beadministered in such a way as to prevent hydrolysis prematurely asdescribed above. Agents that adjust the level of hyaluronic acid intissue are also indicated for enhancing the quality of tissue.

Systemic administration of nutrients is especially important as is thetreatment of viral infection, bacterial infection or other microbialinfection using standard methods. Other applications include modulationof hair growth and treatment of nail disorders as further describedabove. For smoking cessation, one active ingredient is cytisine, alsoknown as baptitoxine and sophorine, and is an alcohol that occursnaturally in several plant genera. It is available commercially.

Suitable active agents to be delivered in using the formulations fortreatment of post procedural bruising include helenalin, asesquiterpene, a lactone as well as Vitamin K. The formulation based onhelenalin may be accompanied by irradiation with light of wavelength577-595 nm. Other active agents include Botox®, flavonoids, skinlighteners and materials that promote collagen biosynthesis.

In all cases, once the application has been made to an appropriate skin,nail or hair follicle area, the area can be sealed with a compositioncomprising linoleic acid.

One particular application is localized fat removal using, for example,bile salts as active ingredients. In this instance, the level oflecithin organogel present in the composition may be lower than in theremaining formulations. The administration of the bile salt or bile acidto remove fat may be accompanied by administration of anestheticregardless of the method of delivery of the fat-dissolving compound.

Thus, the invention is directed to compositions with the penetrants ofthe invention as effective aids in transdermal delivery.

The following examples are provided to illustrate but not to limit theinvention.

Example 1 Dose Dependence of Pain Relief

Compositions were prepared that comprised lidocaine in varying amountsincluding 4.0%, 10%, 15%, and 30% w/w. The compositions also comprisedbenzyl alcohol in an amount of 2% w/w and lecithin isopropyl palmitatein an amount of 22% w/w. The remainder was a stock cream formulationsuch as that sold as VaniCream™. No poloxamer was included in thecomposition.

Ultherapy, which is focused ultrasound, was used to induce pain. Painwas induced at varying depths on the forearms of two male subjects, andcompared to pain on an area of the arm of the test subjects that was nottreated with the composition. The subjects were treated with the varioustransducers at three levels, 1.5 mm, 3.0 mm and 4.5 mm. Pain wasmeasured using the visual analog (VAS) pain scale, which is a validatedpain scale in which test subjects rank pain on a scale of 0 to 10,1-3=very minor, 4-6=minor but tolerable, 7>=painful. Below are theaveraged pain results:

Lidocaine No Lidocaine Dose 1.5 mm 3.0 mm 4.5 mm 1.5 mm 3.0 mm 4.5 mm 4%3.13 4.75 6.25 7.50 9.00 9.50 10% 3.13 4.75 6.25 7.00 8.50 9.34 15% 3.134.75 5.75 6.63 8.00 9.17 30% 2.13 3.75 5.5 6.25 7.50 9.00

By comparing these measurements of pain as measured with thecompositions and without the compositions, the percentages of painattenuation were determined as provided below:

Dose 1.5 mm 3.0 mm 4.5 mm 4% 58% 47% 34% 10% 55% 44% 33% 15% 53% 41% 37%30% 66% 50% 39%

The conclusion based on these data is that pain attenuation was dosedependent because higher pain attenuation resulted from higher doses oflidocaine. Additionally, the pain attenuation was depth dependentbecause as the depth increased, there was less pain attenuation.

Example 2 Compositions Containing Detergent

Compositions were prepared that comprised lidocaine in varying amountsincluding 4.0% and 30% w/w. The compositions also comprised benzylalcohol in an amount of 2% w/w, lecithin isopropyl palmitate in anamount of 22% w/w. In composition #1, poloxamer PEG/propylene glycol(20% w/w by volume of solution) was used top off the composition to 100%by weight of the composition. In composition #2, Aquaphor® sold byEucerin® was used to top off the benzyl alcohol and lecithin isopropylpalmitate instead of poloxamer. Ultherapy was used to induce pain andthe pain was measured using the VAS scale. Pain was induced at varyingdepths on three test subjects.

Below are the measured pain results for compositions #1 and #2 using 30%w/w lidocaine on subject A:

1.5 mm 3.0 mm 4.5 mm #1 2.50 0.50 1.50 #2 3.50 2.00 3.50

Below are the measured pain results for compositions #1 and #2 using 30%w/w lidocaine on subject B:

1.5 mm 3.0 mm 4.5 mm #1 0.50 — 3.00 #2 4.50 — 6.00

Below are the measured pain results for compositions #1 and #2 using 4%w/w lidocaine on subject C:

1.5 mm 3.0 mm 4.5 mm #1 2.50 1.00 2.00 #2 7.00 3.00 5.00

Pain was also measured and averaged, as provided below, on an area ofthe arm of the test subjects that was not treated with the compositions.

Below are the measured pain results on subject A on area not treatedwith the composition:

1.5 mm 3.0 mm 4.5 mm #1 6.00 5.50 8.00 #2 6.00 5.50 8.00

Below are the measured pain results on subject B on area not treatedwith the composition:

1.5 mm 3.0 mm 4.5 mm #1 7.50 6.00 8.00 #2 7.50 6.00 8.00

Below are the measured pain results on subject C on area not treatedwith the composition:

1.5 mm 3.0 mm 4.5 mm #1 8.50 5.50 8.00 #2 8.50 5.50 8.00

By comparing these measurements of pain as measured with thecompositions and without the compositions, the percentages of painattenuation were determined as provided below.

Subject A's percentage of pain attenuation:

1.5 mm 3.0 mm 4.5 mm #1 58% 91% 81% #2 42% 64% 56%

Subject B's percentage of pain attenuation:

1.5 mm 3.0 mm 4.5 mm #1 93% 100% 63% #2 40% 100% 25%

Subject C's percentage of pain attenuation:

1.5 mm 3.0 mm 4.5 mm #1 71% 82% 75% #2 18% 45% 38%

The conclusion based on these data is that the use of poloxamer withlecithin isopropyl palmitate unexpectedly increased pain attenuation atall depths and independent of lidocaine concentration.

Example 3 Effect of Lecithin Organogel Concentration

Compositions were prepared that comprised lidocaine in an amount of 5.0%w/w. The compositions also comprised benzyl alcohol in an amount of 2%w/w, lecithin isopropyl palmitate in amounts of 30%, 40%, 50% and 60%w/w, and the composition was topped off with poloxamers to yield 100% ofthe composition w/w. Pain was induced using an 18 gauge needle with alength of one inch. Pain was measured using the VAS pain scale.

Below are the depths to which the needle was inserted on the forearm ofa subject:

Formulation 30% 40% 50% 60% 5 minutes 20 mm 26 mm 26 mm 26 mm 8 minutes22 mm 26 mm 26 mm 26 mm 10 minutes  22 mm 26 mm 26 mm 26 mm Surface pinpricks 1-2 2-2 2-2 2-3

The tests showed that using lecithin isopropyl palmitate with poloxamerincreased the pain attenuation at all depths and was independent oflidocaine concentration. Further, the tests showed that increasing theamount of lecithin isopropyl palmitate to 40% w/w resulted in an abilityto penetrate the needle more deeply with tolerable pain. Qualitativesurface pin pricks showed that there was some pain, which indicates thatthe composition quickly permeated to greater depths.

Example 4 Delivery of Anesthetic

Pain attenuation was compared using compositions with amounts oflecithin isopropyl palmitate of 0.6%, 20%, 40% and 60% w/w. Thecompositions included 5% lidocaine. Each composition is topped off withpoloxamer (20% solution) to yield a thermogel emulsion with the rheologyof a cream.

The compositions were applied to the forearms of two test subjects foreither 5 minutes or 10 minutes after which pain was induced a 4.5 mmdepth using focused ultrasound. Data were averaged for the two testsubjects as shown below. Pain was tested without any composition on theskin as a control.

For 5 minutes of application:

0.6% 20% 40% 60% Active Control Control Control Control 9 10 10 Active 810 Active 7 10 Active 4 Pain rating 11% −25% −38% −50% % decreased

For 10 minutes of application:

0.6% 20% 40% 60% Active Control Active Control Active Control 8 9.3 8.36.5 8 Active 5 Control 9 5.8 Pain rating 16% −21% −38% −36% % decreased

The amount of pain decreased as the lecithin isopropyl palmitateincreased. Forty percent (40%) lecithin isopropyl palmitate vs. 60% maybe advantageous as it provides ability to add more poloxamer so that thecomposition has more gel-like properties.

Example 5 Delivery of Anesthetics Using the Compositions of theInvention

All of the formulations and protocols below are of the presentinvention.

The following protocol was employed:

1. Cleanse skin, rinse and pat dry;

2. Exfoliate skin with a mild exfoliator (e.g., Offects® ExfoliatingPolish from ZO® Skin Health), rinse off, pat dry;

3. Skin stripping: use clear packing tape, place on skin and strip awayto remove dead skin cells;

4. Occlusion: Place formulation on skin, cover with plastic wrap, suchas Saran™ Wrap, leave on for 15-20 minutes, then remove plastic wrap,clean off any remaining cream;

5. Assess pain and pain mitigation: conduct procedure. Have subjectself-assess pain first in an untreated area to provide context, then inthe treated area. Use the VAS pain scale (0-10), where 0 is no pain and10 is very intense pain.

The manner of inflicting pain was as follows. In all cases, pain wasassessed in untreated areas which are subjected to the same pain stimulifor comparison.

1. Laser: use PaloVia™ hand-held Skin Renewing Laser™ (made by PalomarMedical Technologies, now part of Cynosure, Inc.). Set to highestsetting, fire 1-2 pulses to experience pain.

2. Needles: use 20 gauge needle to create pinpricks on skin. Use 18gauge needle for deep needle test: push needle through skin of forearmand push in up to 25 mm.

3. Ultherapy: override default setting and re-set machine to highestenergy level. Fire 3 cycles first at the 4.5 mm depth, then 3.0 mmdepth, then 1.5 mm depth. Record pain at each level for treated skin.

4. Deoxycholic acid (DCA) injection 10 mg/mL: inject 0.2 mL (2 mg) intoabdomen.

The results are as shown in the chart below; a semicolon indicatesseparate sessions. In general, the pain rating for untreated areas was9-10.

Abbreviations Used

B=benzocaine, L=lidocaine, T=tetracaine,

epi=epinephrine,

BA=benzyl alcohol;

LIP=soy lecithin isopropyl palmitate organogel.

All formulations have 30% LIP, and are QS (topped off) with pluronic 30%w/w aqueous solution.

DCA injection is of bovine source DCA (Kybella™ injection for submentalfat uses a synthetically-derived version of DCA).

Pain scores represent averages to date using the VAS pain chart (0-10)BLT=benzocaine 20%, lidocaine 6%, tetracaine 4% (all w/w).

BLT (20/6/4)+epi=benzocaine 20%, lidocaine 6%, tetracaine 4%,epinephrine 0.01% (all w/w).

In particular experiments, steps 1-3 above were followed, lidocaineand/or tetracaine was applied first, covered with Saran™ Wrap and after10 minutes, followed by uncovering and applying benzocaine and coveringagain, for 10 minutes followed by removing Saran™ Wrap, cleansing skinand following step 5 above.

TABLE 1 DCA injection (10 mg/mL) Ultherapy 0.2 mL pH Laser Needles 1.53.0 4.5 (2 mg)/dose Average B 20%, L 6%, T 4%, BA 2%, pH 10 10 2.5 3.252.5 2 3 2.7 2.7 B 20%, L 6%, T 4%, epi 0.01%, BA 2%, pH 5 5 0.8 2.5 3.30.5 1 1.4 1.6 B 20%, L 6%, T 4%, epi 0.01%, BA 2%, pH 10 10 B 20%, L 6%,T 4%, epi 0.01%, BA 0.9%, pH 5 5 B 20%, L 6%, epi 0.01%, BA 2%, pH 5 5 B20%, L 6%, epi 0.01%, BA 0.9%, pH 5 5 B 20%, epi 0.01%, BA 0.9%, pH 5 52.7 2.8 2 0.5 1.5 1.8 1.9 B 20%, BA 2%, pH 10 10 2 3.3 3 1.5 4 2.8 B20%, BA 10%, pH 10 10 2 3.3 3 1.5 4 2.8 T 1%, epi 0.01%, BA 0.9%, pH 5 54.25 4.75 7.3 5 4.7 5.2 T 2%, BA 2%, pH 10 10 2.6 2.75 6 3.3 3.3 0.753.1 L 5%, BA 0.9%, epi 0.01%, pH 5 10 2.5 4.7 7.3 5 4.3 4.8 L 5%, BA0.9%, pH 10 5 2 2 5.3 2 2 1.25 2.4

In the following Table 2 the following compositions were used.

3=B 20%, BA 0.97%, LIP 30%, epi 0.01%, pH5

7=T 2%, BA 2%, LIP 30%, pH10

10=L 5%, BA 0.9%, LIP 30%, epi 0.01% pH5

11=epi 0.01%, BA 0.9%, LIP 30%, pH5

12=BLT 20/6/4, BA 2%, LIP 30%, pH10

13=B 20%, BA 0.9%, LIP 30%, pH10

14=B+L 20/20, BA 2%, LIP 30%, pH10

15=L 5%, BA 0.9%, LIP 30%, pH10

All were topped up with 30% Pluronic® in water.

TABLE 2 DCA injection (10 mg/mL) Ultherapy 0.2 mL pH Laser Needles 1.53.0 4.5 (2 mg)/dose Average Products used together BLT 10 + 7 + 3 1 1 87 7 0.3 4.1 B + L 10 + 3 3 2 7.5 7.5 5.8 1 4.5 Epi + Caine stepwisetreatment BLT 11 + 12 10 1.3 3.0 7.4 3.4 4.6 3.9 B 11 + 13 10 1.5 3.88.0 3.3 5.3 4.4 B + L 11 + 14 10 1.6 1.6 6.3 2.3 5.3 3.4 L 11 + 15 101.0 4.6 7.5 2.1 7.1 4.5 BLT 11 + 12′ 10 0.3 0.8 1.6 1.1 2.4 2 1.4 BLT12 + 11 10 0.1 1.4 1.8 0.3 0.5 1.5 0.9 B + L 14 + 11 10 0.8 2.3 2.5 1.52.5 1.9 B + L 14-11′ 10 0.8 1.8 3.0 1.3 2.3 1.8 BLT (12 for 5 min., 11for 5 min.) 10 2.5 4.5 3.8 5.5 4.0 4.1 BLT (12 for 10 min., 11 for 10min.) 10 1.0 1.3 2.8 6.3 3.8 3.0 BLT (12 for 5 min., 11 for 15 min.) 100.8 1.3 3.0 7.0 3.3 3.1 BLT (12 for 15 min., 11 for 5 min.) 10 0.1 0.51.8 6.3 4.5 2.6 B (13 for 20 min., 11 for 20 min.) 10 1.0 2.3 3.3 4.53.8 3.0 L (15 for 20 min., 11 for 20 min.) 10 1.2 2.7 3.3 3.8 2.7 2.7BLT: 12 + 11 (12 for 12 min., 11 for 5 min.) 10 1.5 3.3 3.0 3.8 3.3 3.0BLT: 12 + 11 (12 for 20 min., 11 for 5 min.) 10 0.8 2.5 2.0 2.5 3.3 2.2BLT: 12 + 11 (12 for 5 min., 11 for 5 min.) 10 1.0 2.0 3.0 2.1 4.5 2.5BLT: 12 + 11 (12 for 15 min., 11 for 5 min., 10 0.3 1.5 1.8 1.5 2.2 1.5pain stimulus at minute 35) BLT: 12 + 11 (12 for 30 min., 11 for 5 min.,10 0.2 0.3 1.0 1.8 1.3 0.9 pain stimulus at minute 35) L + B + epi: 15 +13 + 11 (15 for 30 min., 13 for 10 0.8 0.3 2.7 3.7 4.2 2.3 15 min., 11for 15 min.) L + B + epi: 15 + 13 + 11 (15 for 20 min., 13 for 10 2.01.7 3.5 2.8 4.2 2.8 10 min., 11 for 10 min.) L + B + epi: 15 + 13 + 11(15 for 15 min., 13 for 10 2.0 2.2 5.0 5.2 2.5 3.4 10 min., 11 for 5min.) BLT: 12 + 11 (12 for 15 min., 11 for 5 min., 10 0.2 1.3 1.3 3.01.8 1.5 pain stimulus at minute 20) BLT: 12 + 11 (12 for 20 min., 11 for5 min.) 10 0.1 0.2 0.3 1.0 1.0 0.5 BLT: 12 + 11 (12 for 25 min., 11 for5 min.) 10 0.1 0.2 0.3 1.7 0.8 0.6 BLT: 12 + 11 (12 for 30 min., 11 for5 min., 10 0.4 0.7 0.4 1.5 2.0 1.0 pain stimulus at minute 35) BLT: 12 +11 (12 for 35 min., 11 for 5 min.) 10 0.5 1.2 1.2 2.2 2.3 1.5 Cainelayering + epi: L + B + epi (15 + 13 + 11) 10 2 2.3 2.7 3.2 4.3 2.9Layer: L (25 min.), B (25 min.), epi (5 min.) L + B + epi (15 + 13 + 11)10 0.3 1.7 3.3 2.3 4.3 2.4 Layer: L (25 min.), B (15 min.), epi (5 min.)B + L + epi (13 + 15 + 11) 10 2.5 2.3 3.0 1.5 4.7 2.8 Layer: B (25min.), L (25 min.), epi (5 min.) B + L + epi (13 + 15 + 11) 10 0.4 2.33.5 2.5 1.8 2.1 Layer: B (25 min.), L (15 min.), epi (5 min.) Caine wipeoff + epi: L + B + epi (15 + 13 + 11): L (25 min., wipe off), 10 1.0 0.73.0 0.8 3.0 1.7 B (25 min., wipe off), epi (5 min.) L + B + epi (15 +13 + 11): L (25 min., wipe off), 10 0.0 0.9 3.2 1.2 1.2 1.3 B (15 min.,wipe off), epi (5 min.) B + L + epi (13 + 15 + 11): B (25 min., wipeoff), 10 0.0 1.5 3.3 1.5 1.0 1.5 L (25 min., wipe off), epi (5 min.) B +L + epi (13 + 15 + 11): B (25 min., wipe off), 10 0.1 1.8 3.7 0.6 2.21.7 L (15 min., wipe off), epi (5 min.) L + B + epi (15 + 13 + 11): L (5min., wipe off), 10 0.2 1.2 2.2 3.2 0.8 1.5 B (20 min., wipe off), epi(5 min.) B + L + epi (13 + 15 + 11): Layer: B (5 min.), L 10 0.4 1.0 3.21.5 0.8 1.4 (20 min.), epi (5 min.) BLT + epi wipe time test: BLT (12)(20 min.) + epi (11) (5 min.): 10 0.3 0.3 1.0 0.8 0.9 0.6 15 min. afterwipe BLT (12) (20 min.) + epi (11) (5 min.): 10 0.5 1.0 0.5 2.5 0.9 1.130 min. after wipe BLT (12) (20 min.) + epi (11) (5 min.): 10 N/A 1.51.5 0.9 2.5 1.6 45 min. after wipe BLT (12) (20 min.) + epi (11) (5min.): 10 N/A 1.0 0.8 1.8 2.8 1.6 75 min. after wipe BLT (12) (20min.) + epi (11) (5 min.): 10 N/A 2.0 3.0 3.5 4.0 3.1 105 min. afterwipe BLT (12 + 11) (12 for 20 min., then 11 for 10 0.3 1.3 2.0 2.7 2.51.8 5 min., then wiped off, then tested at 30 min.) B + L + epi: (13 for5 min., then wipe off, then 10 1.25 3 4.5 3 4.5 3.3 15 for 5 min., thenepi for 5 min., then wipe off, then tested at 30 min.) B + L + epi: (13for 10 min., then wipe off, then 10 0.85 2.25 3 2.5 4 2.5 15 for 10min., then epi for 5 min., then wipe off, then tested at 30 min.)

In Table 3, the listed epinephrine was incubated for 72 hours withDesferal®, an iron chelator. All are QS with 30% Pluronic®. Thecompositions used are:

16=BLT 20/6/4 Desferal® 0.1%, BA 2%, epi 0.01%, LIP 30%, pH10;

17=B 20%, Desferal® 0.1%, BA 0.9%, epi 0.01%, LIP 30%, pH10; and

18=L 5%, Desferal® 0.1%, BA 0.9%, LIP 30, epi 0.01%, pH10.

TABLE 3 DCA injection (10 mg/mL) 0.2 mL pH Laser Needles Ultherapy (2mg)/dose Average BLT: 16 (16 for 20 min.) 10 0.1 0.2 1.3 1.7 1.8 1.0BLT: 16 (16 for 30 min.) 10 0.3 0.7 2.0 1.8 1.5 1.3 L + B: 18 + 17 (18for 20 min., 17 for 10 min.) 10 0.5 1.7 2.8 3.0 2.8 2.2 BLT w/Desferal ® wipe time test: BLT w/ Desferal ® (25 min.): tested at 15min. 10 0 0.4 0.5 3.0 2.3 1.2 after wipe BLT w/ Desferal ® (25 min.):tested at 30 min. 10 0 1.5 0.8 1.0 3.8 1.4 after wipe BLT w/ Desferal ®(25 min.): tested at 45 min. 10 N/A 1.5 1.5 3.3 1.8 2.0 after wipe BLTw/ Desferal ® (25 min.): tested at 75 min. 10 N/A 1.6 1.5 1.8 2.6 1.9after wipe BLT w/ Desferal ® (25 min.): tested at 105 min. 10 N/A 1.13.0 4.8 5.0 3.5 after wipe

Anhydrous Formulations.

In Table 4, all compositions were QS with powdered Pluronic®. Thecompositions used are:

19=BLT 20/6/4, epi 0.01%, Desferal® 0.1%, BA 0.9%, LIP 30%, DCA 6%,pH10;

20=B 20%, epi 0.01%, Desferal® 0.1%, BA 0.9%, LIP 30%, DCA 6%, pH10;

21=L 5%, epi 0.01%, Desferal® 0.1%, BA 2%, LIP 30%, DCA 6%, pH10; and

22=BLT 20/6/4, BA 2%, LIP 30%, DCA 6%, pH10

TABLE 4 DCA injection (10 mg/mL) 0.2 mL pH Laser Needles Ultherapy (2mg)/dose Average BLT (19 for 20 min., then wiped off, tested at 10 1.22.5 3.7 4.7 3.3 3.1 30 min.) BLT (19 for 30 min., then wiped off, testedat 10 1.5 2.2 3.5 3.8 3.5 2.9 30 min.) B + L (20 for 5 min., then wipedoff, then 21 for 10 1.2 2.2 3.7 4.7 2.5 2.8 20 min., then wiped off,then tested at 30 min.) BLT 22 for 20 min., then epi (11) for 5 min., 100.75 2.25 7 5.5 6 4.3 then wipe off, then tested at 30 min.

Example 6 Treatment of Crow's Feet

Two subjects were treated to smooth-out crow's feet thus enhancing thetissue volume next to the eye.

In both cases, the skin next to the eye was cleansed and exfoliatedusing sticky tape and cleansed with isopropyl alcohol. A formulationcontaining 65% w/w of Pluronic® lecithin organic gel made up of 33.17%poloxamer 407 powder, 33.17% soy lecithin granules, and 33.17% isopropylpalmitate syrup was mixed with 2% w/w benzyl alcohol and buffer to pH10-11 wherein the buffer comprises 10 g sodium bicarbonate and 12.6 g ofsodium carbonate along with 0.5 g of sorbate acid as a preservative.This was applied and allowed to remain for 20 minutes, and then wipedoff. Zero point six-five (0.65) ml of a formulation comprising theabove-buffered composition along with 9 g per 100 g of composition—i.e.,90 mg/ml of glutaric anhydride was applied and allowed to remain for 30minutes. The formulation was then wiped off and the results evaluated 15minutes later. FIGS. 1A and 1B show the results for the first subjectwherein FIG. 1A shows the subject prior to treatment and FIG. 1B showsthe subject 15 minutes subsequent to treatment. FIGS. 2A and 2B show theeffects were still in place after about 4 months as shown in FIG. 2B.

FIGS. 3A and 3B show comparable results before treatment and 15 minutessubsequent for the second subject.

Example 7 Photographic Description of Individual Patient Results

An individual subject was administered a topical cream comprising 22%w/w deoxycholic acid; 0.8% w/w phosphatidylcholine, 1% w/w caffeine,0.5% w/w arginine; 0.5% w/w L-carnitine, 2% w/w benzyl alcohol, 30% w/wlecithin isopropyl palmitate; and brought to 100% with an aqueoussolution of 30% poloxamer. The cream was applied thinly to the areab.i.d. covered with Saran™ Wrap and held in place for 30 minutes. Beforetreatment, as indicated in FIGS. 4A and 5A, the dimensions of the fatdeposit were 6.1×4.7 cm with the surface area of 22.5 cm². The height ofdeposit was 1.2 cm and the deposit was firm and clearly delineated.After 12 days, as shown in FIG. 4B, the dimensions had been reduced to4.6×3.1 cm with a surface area of 12.2 cm² (a reduction of 50%) theheight was reduced to 0.8 cm or reduction of 33%, and the deposit wassofter and to borders were more difficult to define.

As shown in FIG. 5B after one month, the dimensions were reducedslightly more to 4.3×2.2 cm with a surface area of 7.1 cm² or an areareduction of about 67%. The height was clearly reduced to 0.5 cm or 58%reduction. The deposit was even softer and the borders even moredifficult to define.

Example 8 Relief of Lactic Acidosis

A single subject was used in this test. One forearm was treated with aformulation which comprises:

11% w/w CarboPro® (a mixture of complex carbohydrates from variousplants);

11% w/w sodium bicarbonate;

11% w/w whey protein powder;

1% w/w benzyl alcohol;

27% w/w soy lecithin isopropyl palmitate;

remainder 30% w/w Pluronic® (poloxamer) in water.

The other forearm was left untreated.

Acidosis was induced by having the subject perform 60 forearm flexionsat the rate of 1 per second using a resistance band. This was repeatedevery 5 minutes. The subject was asked to report a burning sensationwhen acidosis occurred. The number of flexions the subject was able toperform at each 5-minute interval before experiencing burn was testedfor each arm.

The first set was performed 5 minutes after treatment. The results wereas follows.

Number of Flexions Treated Untreated Time 0 16 16  5 minute set 16 16 10minute set 18 14 15 minute set 50 10 20 minute set 40 5 25 minute set 305 30 minute set 25 4Thus, over the course of the test, the treated arm could perform 195repetitions as compared to 70 for the untreated. It appeared that thetime for absorption of the formulation was between 10 and 15 minutes; ifthe last three timepoints after that were the only ones considered, thecomparison was 120 for the treated arm vs. 20 for the untreated.

Example 9 Acidosis Test Without Nutrients

In another experiment designed to test the ability of the formulation toimpede lactic acidosis, again a single subject was used with one armtreated with a formulation containing:

33% w/w sodium bicarbonate;

1% w/w benzyl alcohol;

25% w/w soy lecithin isopropyl palmitate;

made up to 100% w/w with a 30% w/w solution of Pluronic® in water.

In this exercise, a “preacher curl” exercise with a fixed weight wasemployed and the number of repetitions performed by each arm before thesubject reported failure due to burning was recorded. At the 0timepoint, both arms performed approximately 50 repetitions; however, inthe 10 minute exercise set, the treated forearm performed 77 as comparedto 52 by the untreated arm; in the 20 minute set the treated forearmperformed 62 compared to 46; and at 30 minutes, the treated forearmperformed 44 as compared to 30 by the control.

Assuming absorption at 10 minutes, the total repetitions in the workoutsat 10, 20 and 30 minutes were 183 for treated vs. 128 for untreated.Overall the total was 235 for treated vs. 176 for untreated.

Example 10 Lactic Acidosis Test Using Sodium Bicarbonate Plus Nutrients

Six individuals were used in this test, each having a treat calf and anuntreated calf as a control.

The treatment formulation was:

1% w/w beta alanine;

4% w/w sodium bicarbonate;

1% w/w L-carnitine;

1% w/w adenosine triphosphate;

24% w/w dextrose;

1% w/w creatine monohydrate;

0.4% w/w beta-hydroxy-beta-methylbutyrate;

2% w/w branched chain amino acids (leucine, isoleucine, valine, 1:1:1);

1% w/w glutathione;

30% w/w soy lecithin isopropyl palmitate;

2% w/w benzyl alcohol;

Q.S. with 30% w/w poloxamer in water.

In this example, the exercise was calf flexion/heel raises 1 per 2seconds repeated every 5 minutes. In this case, the control containedthe penetrant alone. The results are shown in FIG. 6A-C. FIG. 6A showsthe relative time to acknowledging lactic acidosis burn; FIG. 6B showsthe relative time to notice pain and FIG. 6C shows the relative maximumnumber of repetitions. In each case these are calculated based on a 100%value at time zero.

As shown, there was a significant increase in the time until acidosisburn occurred and an increase in the time before threshold pain wasfelt. The maximum number of repetitions that could be performed was alsomeasured and showed an increase for the treated legs. The results areshown as a percentage of performance at time zero.

Example 11 Systemic Glucose Absorption

A single subject was used in this study. After an overnight fast, 24 mgof a dextrose formulation in cream was applied to the upper body of theindividual by a massage. The formulation was:

50% w/w dextrose;

1.3% w/w benzyl alcohol;

28% w/w soy lecithin isopropyl palmitate;

Q.S. with 30% w/w poloxamer in water.

The results were similar to those obtained with i.v. dextrose infusion.The blood glucose level in mg/dL was measured with a One-Touch Ultra®blood glucose meter. At time zero, the reading was 90 mg/dL but after 15minutes the blood glucose level rose to almost 200 mg/dL and thendeclined by 50 minutes subsequent to the application of the formulationto about 100 mg/dL which was maintained at substantially this level forover 2 hours.

In addition, the subject, after the overnight fast, reported feelinghungry and wanting to eat, but 15 minutes after application of theformulation, the subject noted feeling completely satiated.

In addition, two additional subject who expressed hunger were able toassuage this hunger by application of the formulation described herein.

Example 12 Relief from Lactic Acidosis (Alternate Exercise Regime)

In this test, the formulation was:

40% w/w sodium bicarbonate;

1.7% w/w benzyl alcohol;

36% w/w soy lecithin isopropyl palmitate;

Q.S. 30% w/w poloxamer, buffered to pH 10-11.

In this example, the subjects were assigned 5 sets of pushups—to do asmany as possible. The interval between sets was 3 minutes and 30seconds. The formulation was applied 15 minutes prior to and immediatelybefore the first set.

Three subjects participated in the test. Controls were performed bytesting the three subjects without treatment, then waiting three daysand treating the three subjects and testing them again. Two such seriesof tests were performed. Thus, on day 1 the three subjects performed thepushups at the indicated time intervals without having been treated; onday 4 the three subjects were treated as described and then performedthe pushup sets at the indicated intervals. On day 7 the subjects wereagain not treated but performed the required exercises and on day 10 theexercises were performed after treatment as described above. The resultsare shown in FIG. 7 which is a graph showing the average repetitions forall three subjects at each set.

Improvement at each set was shown, particularly in the middle set beforeexhaustion was reached. Thus, in the first series of experiments, theimprovement at set 1 was 6%, at set 2 was 18%, at set 3 was 33%, at set4 was 19% and at set 5 was 7%, with the overall improvement in totalsacross all five sets at 15%. When the experiment was repeated, i.e., inthe second series of tests, the controls performed better than thecontrols in the first set. Based on 100% performance on the first set bycontrols, the controls performed at 114%, but when treated in thissecond test, their performance level was 128% of the original controlsshowing an improvement of 14% over the corresponding controls in thesecond set.

Example 13 Stimulation of Hair Growth

The subject in this example exhibits male pattern baldness. Thecomposition applied was 0.015% w/w bimatoprost from 0.03% commerciallyavailable Latisse® by 0.015% w/w bimatoprost, 2% w/w benzyl alcohol, 33%w/w soy lecithin isopropyl palmitate topped off with 20% Pluronic® inaqueous solution for 4 weeks. The composition was applied to the scalpat a level of 0.1 ml/2 cm² b.i.d.—i.e., twice per day. The results wereassessed after this time.

FIGS. 8A and 8B show generally the scalp of the treated subject with thetreated area and untreated area delineated before (FIG. 8A) and after(FIG. 8B) 4 weeks.

FIGS. 9A and 9B show a comparison of the treated area before (FIG. 9A)and after (FIG. 9B) treatment over the 4 week period.

As shown, the hair follicles existing at the beginning of treatmentremained at the end of treatment, but the hair was thicker and darker inthe treated portion. In addition, the lighter circles in FIG. 9Bindicate new hair growth from follicles not previously seen. The darkercircles indicate the existing hair. Overall, the existing hair wasrepresented by 18 strands and there were 8 strands of new hair.

This is in contrast to the untreated area of the same scalp which isshown in FIG. 10A (before treatment) and FIG. 10B (the untreated portion4 weeks later). Again, the circles indicate the location of hairfollicles before and after. As seen, the existing hair before the startof the experiment represented 22 follicles and 2 of these were lost inthe untreated portion.

Example 14 Stimulation of Hair Growth by 0.3% w/w Bimatoprost

Two subjects that exhibited male pattern baldness were used in thisexample. The composition applied was 0.3% w/w bimatoprost, 1% benzylalcohol, 33% soy lecithin isopropyl palmitate organogel topped to 100%with 30% poloxamer at pH 7.8. The 30% poloxamer is Pluronic® in aqueoussolution. One ml was applied over the entire crown twice a day over a 7week period. Subjects were photographed each week as shown in FIGS. 11Aand 11B. In each case, for photography, the hair was trimmed (to ⅛ of aninch) a day prior to the pictures. The global photographs were takenwith an Apple iPhone 6s using a desk-mounted tripod and a stereotactichead positioning device under standardized lighting conditions.

FIGS. 12A and 12B show enlarged views of the overall hair growth after 7weeks for each of the subjects.

In addition, similar to the procedure in Example 13, 1 cm² areas of thescalp of each subject were photographed and the number of hair folliclescounted at 4 weeks for each subject. The results for subjects 1 and 2are shown below in Table 5 and Table 6.

TABLE 5 Subject 1 Follicles per cm² Baseline Lost Gained Final Netchange 10 0 4 14 40% 14 5 9 18 29% 23 10 14 27 17% Average 15.7 5.0 9.019.7 25.5%  

TABLE 6 Subject 2 Follicles per cm² Baseline Lost Gained Final Netchange 6 2 7 11 83% 13 8 12 17 31% 8 3 3 8  0% Average 9.0 4.3 7.3 12.033.3%  

As shown, considerable variation depending on the sample area selectedis shown, but subject 1 showed an overall increase in hair follicles of25.5% over 4 weeks and subject 2 showed an overall increase of 33.3%hair follicles over 4 weeks.

While the sampling in Example 13 was limited, it appears that comparableresults were achieved whether the bimatoprost was used at 0.015% as inExample 13 or at 0.3% as in Example 14—after 4 weeks the sample selectedin Example 13 showed a 44% increase. In addition, in Example 13 only 0.1ml was applied per cm² whereas in Example 14 1 ml of formulation wasapplied per cm². The essentially flat dose response curve isadvantageous in view of the known induction of undesirable side effectswith higher concentrations of bimatoprost in commercial preparations.

In addition, as compared to published studies with commerciallyavailable Rogaine™, the results appear to achieve at 4-7 weeks whatRogaine™ requires 12 months of treatment to obtain. Indeed, thesestudies showed evidence of hair growth was not demonstrated until after8 months of treatment with concentrations of 2% and 5% of minoxidil.

Example 15 Regrowth of Hair Lost in Chemotherapy

Compositions were prepared that comprise bimatoprost in varying amountsincluding 4.0%, 10%, 15%, and 30% w/w. The compositions also comprisedbenzyl alcohol in an amount of 2% w/w and lecithin isopropyl palmitatein an amount of 30% w/w. The remainder was a stock cream formulationsuch as that sold as VaniCream™. No poloxamer was included in thecomposition.

Example 16 Compositions Containing Detergent

Compositions were prepared that comprised minoxidil in varying amountsincluding 4.0% and 30% w/w. The compositions also comprised benzylalcohol in an amount of 2% w/w, lecithin isopropyl palmitate in anamount of 40% w/w. In composition #1, poloxamer PEG/propylene glycol(20% w/w by volume of solution) was used top off the composition to 100%by weight of the composition. In composition #2, Aquaphor® sold byEucerin® was used to top off the benzyl alcohol and lecithin isopropylpalmitate instead of poloxamer.

Example 17 Effect of Lecithin Organogel Concentration

Compositions were prepared that comprised minoxidil in an amount of 5.0%w/w. The compositions also comprised benzyl alcohol in an amount of 2%w/w, lecithin isopropyl palmitate in amounts of 30%, 40%, 50% and 60%w/w, and the composition was topped off with aqueous solutions ofpoloxamers to yield 100% of the composition w/w.

Example 18 Treatment of Onychomycosis

A. The formulation used in this example is 10% terbinafine (an allylamine antifungal of the structure

2% benzyl alcohol, 40% lecithin isopropyl palmitate (LIP), 13.4%poloxamer and the remainder water. The composition contains theterbinafine in a micellular support system generated by the carrier. Theformulation (5 ml) was applied to toenails exhibiting onychomycosis ofthree individuals twice daily for a period of three weeks. After eachapplication, a band-aid was placed over the area of application for onehour to prevent loss and to encourage penetration.

After three weeks of the treatment, the fungal condition of eachindividual had cleared. This is shown in FIGS. 13A-B, 14A-B and 15A-B.As shown for example in FIG. 14A-B, nail growth occurred over this timeand the infected nail lifted after three weeks and revealed healthy nailgrowth underneath. This is in contrast to the commercially availableJublia® topical which requires 48 weeks of treatment for positiveresults.

B. The treatment protocol of paragraph A is performed but using, in theformulation on a weight basis, 1% terbinafine, 5% terbinafine, 15%terbinafine or 20% terbinafine. The remaining components are present atthe same concentrations as in paragraph A. The formulations are appliedto fingernails exhibiting onychomycosis as described in paragraph A andon the same schedule.

C. The procedure of paragraph A is followed except the poloxamer isomitted from the formulation. The formulation is applied to the affectednails and immediately covered with adhesive tape which remains incontact with the nail for 30 minutes. After two weeks of dailyapplication, the results are evaluated.

D. The procedure of paragraph B is performed except that poloxamer isomitted from the formulation. The formulation is applied to the affectednails, covered with masking tape and left in contact for 15 minutes. Theprocedure is repeated every other day for six weeks and the results areevaluated.

E. The procedure of paragraphs A-D are performed but substituting forterbinafine, alternate allyl amines.

F. The procedure of paragraphs A-D are performed but substituting forterbinafine, fenticonazole, ravuconazole, caspfungin, ciclopirox,flucytosine or undecylenic acid.

G. The procedures of paragraphs A-D are performed but substituting forterbinafine one of the antifungal fluconazole, aculeacin A(echinocandin) or tavaborole. In each case, the results are evaluatedvisually.

H. The procedures of paragraphs A-D are performed but using acombination of 5% w/w fluconazole and 5% w/w terbinafine as activeingredients.

The procedures of A-H are performed except the formulation isadministered to areas of the skin beyond the toe that exhibit fungalinfection.

Example 19 Treatment of Psoriasis

A. The formulation used in this example is on a weight basis: 5% of theanti-inflammatory diclofenac, 1% benzyl alcohol, 30% lecithin isopropylpalmitate (LIP), 18% poloxamer and the remainder water. The compositioncontains the diclofenac in a micellular support system generated by thecarrier. The formulation (5 ml) is applied to nails exhibiting psoriasistwice daily for a period of three weeks. After each application, animpermeable cover was placed over the area of application for 0.5 hoursto prevent loss and to encourage penetration. After two weeks of thetreatment, the results are evaluated.

B. The procedure of paragraph A is followed except that theanti-inflammatory celecoxib was substituted for diclofenac.

C. The procedure of paragraph A is followed except that the diclofenacis supplied at 5% w/w, 15% w/w or 20% w/w.

D. The procedure of paragraphs A-C is performed except that theformulation contained no poloxamer.

E. The procedure of paragraphs A-C is performed except that thepercentage of poloxamer is 10% w/w.

F. The procedure of paragraphs A-E is performed except that the agent isapplied to areas of the skin that exhibit psoriasis

Example 20 Treatment of Onychomycosis

A. The formulation used in this example is 4% efinaconazole, 2% benzylalcohol, 40% lecithin isopropyl palmitate (LIP), 13.4% poloxamer and theremainder water. The composition contains the efinaconazole in amicellular support system generated by the carrier. The formulation (5ml) is applied to toenails exhibiting onychomycosis of three individualstwice daily for a period of three weeks. After each application, aband-aid is placed over the area of application for one hour to preventloss and to encourage penetration.

B. The treatment protocol of paragraph A is performed but using, in theformulation on a weight basis, 1% efinaconazole, 5% efinaconazole, 15%efinaconazole or 20% efinaconazole. The remaining components are presentat the same concentrations as in paragraph A. The formulations areapplied to fingernails exhibiting onychomycosis as described inparagraph A and on the same schedule.

C. The procedure of paragraph A is followed except the poloxamer isomitted from the formulation. The formulation is applied to the affectednails and immediately covered with adhesive tape which remains incontact with the nail for 30 minutes. After two weeks of dailyapplication, the results are evaluated.

D. The procedure of paragraph B is performed except that poloxamer isomitted from the formulation. The formulation is applied to the affectednails, covered with masking tape and left in contact for 15 minutes. Theprocedure is repeated every other day for six weeks and the results areevaluated.

H. The procedures of paragraphs A-D are performed but using acombination of 5% w/w efinaconazole and 5% w/w terbinafine and/orfluconazole as active ingredients.

Example 21 Treatment of Athlete's Foot

A. The formulation used in this example is 10% terbinafine, 2% benzylalcohol, 40% lecithin isopropyl palmitate (LIP), 13.4% poloxamer and theremainder water. The composition contains the terbinafine in amicellular support system generated by the carrier. The formulation (35ml) is applied twice daily for a period of four weeks to the skin of thefeet of four individuals exhibiting the symptoms of athlete's foot.After each application, a covering is placed over the area ofapplication for one hour to prevent loss and to encourage penetration.After four weeks of the treatment, the athlete's foot symptoms areameliorated.

B. The treatment protocol of paragraph A is performed but using, in theformulation on a weight basis, 1% tavaborole, 5% tavaborole, 15%tavaborole or 20% tavaborole. The remaining components are present atthe same concentrations as in paragraph A. The formulations are appliedto the feet of subjects exhibiting the symptoms of athlete's foot asdescribed in paragraph A and on the same schedule.

C. The procedure of paragraph A is followed except the poloxamer isomitted from the formulation. The formulation is applied to the affectedfeet of subjects exhibiting the symptoms of athlete's foot andimmediately covered with adhesive tape for 30 minutes. After two weeksof daily application, the results are evaluated.

D. The procedure of paragraph B is performed except that poloxamer isomitted from the formulation. The formulation is applied to the affectedfeet of subjects exhibiting the symptoms of athlete's foot, covered withmasking tape and left in contact for 15 minutes. The procedure isrepeated every other day for six weeks and the results are evaluated.

E. The procedures of paragraphs A-D are performed but substitutingefinaconazole for terbinafine or tavaborole.

F. The procedures of paragraphs A-D are performed but substitutingfenticonazole, ravuconazole, caspfungin, ciclopirox, flucytosine orundecylenic acid as the antifungal agent.

G. The procedures of paragraphs A-D are performed but substituting oneof the antifungal fluconazole or aculeacin A (echinocandin) asantifungal agent. In each case, the results are evaluated visually.

H. The procedures of paragraphs A-D are performed but using acombination of 5% w/w fluconazole and 5% w/w terbinafine as activeingredients.

Example 22 Treatment of Jock Itch

A. The formulation used in this example is 4% efinaconazole, 2% benzylalcohol, 40% lecithin isopropyl palmitate (LIP), 13.4% poloxamer and theremainder water. The composition contains the efinaconazole in amicellular support system generated by the carrier. The formulation (5ml) is applied to the groin of subjects showing symptoms of jock itchdaily for a period of two weeks. After each application, a bandage isplaced over the area of application for one hour to prevent loss and toencourage penetration.

B. The treatment protocol of paragraph A is performed but using, in theformulation on a weight basis, 1% efinaconazole, 5% efinaconazole, 15%efinaconazole or 20% efinaconazole. The remaining components are presentat the same concentrations as in paragraph A. The formulations areapplied to the groin of subjects showing symptoms of jock itch asdescribed in paragraph A and on the same schedule.

C. The procedure of paragraph A is followed except the poloxamer isomitted from the formulation. The formulation is applied to the groin ofsubjects showing symptoms of jock itch. After two weeks of dailyapplication, the results are evaluated.

D. The procedure of paragraph B is performed except that poloxamer isomitted from the formulation. The formulation is applied to the groin ofsubjects showing symptoms of jock itch, covered with a bandage and leftin contact for 15 minutes. The procedure is repeated every other day forsix weeks and the results are evaluated.

H. The procedures of paragraphs A-D are performed but using acombination of 5% w/w tavaborole and 5% w/w terbinafine and/orfluconazole as active ingredients.

Example 23 Micelle Production and Milling Procedures

A. The formulation used in this example is 4% lidocaine, 1% menthol,0.9% benzyl alcohol, 30% lecithin isopropyl palmitate, buffered to pH10, and brought to volume with a 30% Pluronic® solution.

B. The formulation was milled using a Dermamill 100 (Blaubrite) usingthe following parameters: X-Y-Z; where X is the speed of the millingmachine rollers from 1 to 100, where 1 is the slowest and 100 is thefastest; Y is pressure from 1 to 5, where 1 is the highest pressure and5 is the lowest pressure; and Z is the number of passes through themilling machine. One pass was considered complete when all of theproduct passed through the machine. For example, a milling procedurerepresented by X-Y-Z, X-Y-Z has the same format as described herein butit has two phases of milling.

Micelle density was examined using an Omano OM88 clinical lightmicroscope and Moticam 1SP microscope camera. Images were captured underlight microscopy at 64× magnification, taking care to ensure that theimages were representative of the entire sample. The images werecentered on a 10×10 grid; each cell containing visible micelles wasmarked, and all the marked cells were counted and the total divided by100 to give the percent density. Representative images are shown in FIG.16A-D.

As shown, increasing pressure (FIG. 16A vs. C or B vs. D) and/orincreasing milling speed (FIG. 16B vs. A or D vs. C) resulted in higherdensity of micelles in general.

Example 24 Micelle Density and Attenuation of Pain Relief

The composition of Example 23 was milled at different values of X-Y-Z.

Ultherapy was used to induce pain at specific depths of 1.5 mm, 3.0 mmand 4.5 mm. The default/maximum power was used for this test.

The formulations were applied on the thighs of two subjects on adjacentareas of close proximity to reduce the likelihood of pain sensitivityvariation. The test was also repeated on 3 other areas: cheeks, upperarms, and lower arms. On either side of each sample, untreated areaswere marked off as control. Each sample was assigned a pain attenuationscore by testing the control on one side, then the sample, and then thecontrol on the other side to account for possible pain sensitivityvariation. Each formula was tested at 1.5 mm, 3.0 mm, and 4.5 mm, on 2subjects. Three (3) depths×2 people=>n=6 test spots for each formula.Each test spot was assessed as a treated area, and 2 untreated controlsdirectly adjacent to the treated area.

Below are the averaged results.

Milling Procedure Micelle Density Pain Attenuation (Average) 100-1-3 77%50%  50-1-3 88% 48% 100-5-3 57% 33%  50-5-3 33% 34%

Micellar density vs. pain attenuation is plotted in FIG. 17.

Thus pain attenuation was correlated with density of micelles.

Example 25 Synergistic Effect on Pain Attenuation Using Two Formulations

A. The formulations used in this example are as follows:

1) 4% lidocaine, 1% menthol, 0.9% benzyl alcohol, 30% lecithin isopropylpalmitate, buffered to pH 10, and brought to volume with a 30% Pluronic®solution, labeled below as “Procicept L.”

2) 20% benzocaine, 1% menthol, 0.9% benzyl alcohol, 30% lecithinisopropyl palmitate, buffered to pH 10, and brought to volume with a 30%Pluronic® solution, labeled below as “Procicept B.”

3) A combination treatment of L and B wherein L is applied first,followed immediately (without wiping off) by B. labeled below as“Procicept L+B.”

B. Ultherapy was used to induce pain at specific depths of 1.5 mm, 3.0mm and 4.5 mm using the protocol of Example 24. The maximum power wasused for this test.

Below are the results, in terms of pain attenuation.

Formulation 1.5 mm 3.0 mm 4.5 mm Average Procicept L 41% 75% 42% 51%Procicept B 35% 39% 32% 35% Procicept L + B 63% 75% 64% 68%

1. A penetrant designed to provide the following components thatcollectively effect transdermal delivery of an active agent in aformulation of such agent: sufficient lecithin organogel, benzylalcohol, surfactant and polar solvent to provide a formulation of saidagent that comprises benzyl alcohol at 0.5-20% w/w of said formulation,lecithin organogel at 25-70% w/w of said formulation, nonionicsurfactant at 2-25% w/w of said formulation and polar solvent at leastin an amount in molar excess of the nonionic surfactant.
 2. A penetrantdesigned to provide the following components that collectively effecttransdermal delivery of an active agent in a formulation of said agent:sufficient lecithin organogel and benzyl alcohol to provide aformulation of said agent, that comprises lecithin organogel at 30%-60%w/w of said formulation and benzyl alcohol at 0.5-20% w/w of saidformulation,
 3. A penetrant designed to provide the following componentsthat collectively effect transdermal delivery of an active agent in aformulation of said agent: sufficient lecithin organogel, benzylalcohol, surfactant, and bile salt to provide a formulation of saidagent that comprises benzyl alcohol at 0.5-20% w/w of said formulation,lecithin organogel at 25-70% w/w of said formulation, nonionicsurfactant at 20-60% w/w of the formulation and bile salt at 1-15% w/wof the formulation, wherein the surfactant is provided in powdered formand the formulation is essentially anhydrous.
 4. A formulation fortransdermal delivery of an active agent through the skin, nail or hairfollicle of a subject, which formulation comprises at least one activeagent in an amount effective for treatment of a condition in saidsubject and the penetrant of claim
 1. 5. A formulation for transdermaldelivery of an active agent through the skin, nail or hair follicle of asubject, which formulation comprises at least one active agent in anamount effective for treatment of a condition in said subject and thepenetrant of claim
 2. 6. A formulation for transdermal delivery of anactive agent through the skin, nail or hair follicle of a subject, whichformulation comprises at least one active agent in an amount effectivefor treatment of a condition in said subject and the penetrant of claim3.
 7. The formulation of claim 4 wherein the lecithin organogel is acombination of soy lecithin with isopropyl palmitate.
 8. The formulationof claim 5 wherein the lecithin organogel is a combination of soylecithin with isopropyl palmitate.
 9. The formulation of claim 6 whereinthe lecithin organogel is a combination of soy lecithin with isopropylpalmitate.
 10. The formulation of claim 4 wherein the nonionicsurfactant is a poloxamer and the polar solvent is water.
 11. Theformulation of claim 4 and/or wherein the formulation has a pH of 9-11.12. The formulation of claim 5 wherein the formulation has a pH of 9-11.13. The formulation of claim 6 wherein the formulation has a pH of 9-11.14. The formulation of claim 4 wherein an active ingredient is ananesthetic, a fat-dissolving agent, a nutrient or nutrient combination,a tissue volume enhancer, a vaccine component, a hair growth modulator,an antifungal agent, an agent to promote smoking cessation, and/or acannabinoid.
 15. The formulation of claim 5 wherein an active ingredientis an anesthetic, a fat-dissolving agent, a nutrient or nutrientcombination, a tissue volume enhancer, a vaccine component, a hairgrowth modulator, an antifungal agent, an agent to promote smokingcessation, and/or a cannabinoid.
 16. The formulation of claim 6 whereinan active ingredient is an anesthetic, a fat-dissolving agent, anutrient or nutrient combination, a tissue volume enhancer, a vaccinecomponent, a hair growth modulator, an antifungal agent, an agent topromote smoking cessation, and/or a cannabinoid.
 17. A method to effecttransdermal delivery of an active ingredient, which method comprisesapplying to the skin, nails or hair follicles of a subject an effectiveamount of the formulation of claim
 4. 18. A method to effect transdermaldelivery of an active ingredient, which method comprises applying to theskin, nails or hair follicles of a subject an effective amount of theformulation of claim
 5. 19. A method to effect transdermal delivery ofan active ingredient, which method comprises applying to the skin, nailsor hair follicles of a subject an effective amount of the formulation ofclaim
 6. 20. The method of claim 17 wherein said treating is of skin andwhich further includes, following said treating, applying a compositioncomprising linoleic acid to the area of treatment.
 21. The method ofclaim 18 wherein said treating is of skin and which further includes,following said treating, applying a composition comprising linoleic acidto the area of treatment.
 22. The method of claim 19 wherein saidtreating is of skin and which further includes, following said treating,applying a composition comprising linoleic acid to the area oftreatment.